Pharmaceutical compositions of dextran polymer derivatives

ABSTRACT

Pharmaceutical compositions are provided comprising an active agent and a dextran polymer derivative. The compositions include from 0.01 to 99 wt % of an active agent and from 1 to 99.99 wt % of a dextran polymer derivative. The dextran polymer derivative is selected from dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, and mixtures thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional PatentApplication No. 61/157,854, filed Mar. 5, 2009, and U.S. ProvisionalPatent Application No. 61/178,690, filed May 15, 2009, each of which isincorporated herein in its entirety by reference.

TECHNICAL FIELD

Pharmaceutical compositions are provided comprising an active agent anda dextran polymer derivative.

BACKGROUND

Pharmaceutically active agents are generally formulated as solid orliquid dosage forms for administration. Such dosage forms generallycomprise the active agent combined with excipients to form materialsthat may be conveniently and reliably administered to a patient in needof such therapy, and following administration, the active agent isabsorbed and distributed in the patient in a way that leads to goodefficacy and safety.

For example, when a low-solubility active agent is dosed orally, it issometimes desired to form a solid amorphous dispersion of the activeagent and a polymer in order to enhance the absorption of the activeagent. One reason for forming solid amorphous dispersions is that theaqueous dissolved active agent concentration of a poorly aqueous solubleactive agent may be improved by forming an amorphous dispersion of theactive agent and a polymer. For example, Curatolo et al., EP 0 901 786B1 disclose forming pharmaceutical spray-dried dispersions of sparinglysoluble drugs and the polymer hydroxypropyl methyl cellulose acetatesuccinate (HPMCAS). Such solid amorphous dispersions of drug and polymerprovide higher concentrations of dissolved drug in an aqueous solutioncompared with the drug in crystalline form. Such solid amorphousdispersions tend to perform best when the drug is homogeneouslydispersed throughout the polymer.

In another example, an active agent is combined with a polymer andformed into nanoparticles, having an effective diameter of less thanabout 400 nm. Such nanoparticles can be used for a wide variety ofdelivery routes, including oral, injectable, ocular, and pulmonarydelivery of the active agent.

For most non-oral delivery routes, it is desired that the excipientsused in the formulation be at least biocompatible, or preferablybiodegradable. However, many of the excipients used in oralformulations, and especially polymers, are not biodegradable orbiocompatible. Those pharmaceutically acceptable polymers that arebiodegradable or biocompatible often do not have the desired or requiredproperties for effectively formulating the active agent into the desiredform. For example, most polymers that can be safely used for parenteraldelivery are highly water soluble. As a result, they are typicallyinappropriate for use in making aqueous suspensions of nanoparticles orother types of dosage forms such as long-acting depots.

What is desired is a pharmaceutical composition comprising an activeagent and a polymer, wherein the polymer has improved properties thatmake the composition suitable for a wide range of applications.

SUMMARY

A pharmaceutical composition comprises from 0.01 to 99 wt % of an activeagent and from 1 to 99.99 wt % of a dextran polymer derivative. Thedextran polymer derivative is selected from dextran acetate, dextranpropionate, dextran succinate, dextran acetate propionate, dextranacetate succinate, dextran propionate succinate, dextran acetatepropionate succinate, and mixtures thereof. In some embodiments, thedextran polymer derivative is selected from the group consisting ofdextran acetate, dextran propionate, dextran succinate, dextran acetatepropionate, dextran acetate succinate, dextran propionate succinate,dextran acetate propionate succinate, and mixtures thereof.

In one embodiment, at least 50 wt % of the composition is comprised ofthe active agent and dextran polymer derivative. In another embodiment,at least 75 wt % of the composition consists essentially of the activeagent and the dextran polymer derivative. In yet another embodiment, atleast 90 wt % of the composition consists essentially of the activeagent and the dextran polymer derivative. In still another embodiment,the composition consists essentially of the active agent and the dextranpolymer derivative.

In one embodiment, the composition comprises a plurality of particlescomprising the active agent and the dextran polymer derivative. Inanother embodiment, the composition is in the form of a coating on asubstrate.

In one embodiment, the composition is in the form of a solid dispersionof the active agent and the dextran polymer derivative, wherein at least90 wt % of the active agent in the dispersion is non-crystalline. Inanother embodiment, at least 90 wt % of the active agent is in the formof a solid solution in the dispersion.

In another embodiment, the composition comprising an active agent andthe dextran polymer derivative is in the form of nanoparticles, whereinthe nanoparticles have an average size of less than 500 nm.

In still another embodiment, a composition comprises (a) nanoparticlescomprising the active agent, wherein the nanoparticles have an averagesize of less than 500 nm; and (b) a resuspending material comprising thedextran polymer derivative; wherein from 5 wt % to 90 wt % of thecombined mass of (1) the nanoparticles and (2) the resuspending materialcomprises the resuspending material.

In yet another embodiment, the active agent is present in the dextranpolymer derivative in a form selected from at least one of crystallineand semi-crystalline active agent having a size of less than 400 nm inat least one dimension.

In one embodiment, the dextran polymer derivative has a total degree ofsubstitution of acetate, propionate, and succinate groups of greaterthan or equal to 0.05. In another embodiment, the dextran polymerderivative has a total degree of substitution of acetate, propionate,and succinate groups of greater than or equal to 0.25.

In yet another embodiment, the composition consists essentially of theactive agent and the dextran polymer derivative.

In yet another embodiment, the dextran polymer derivative is selectedfrom dextran acetate succinate, dextran propionate succinate, dextranacetate propionate succinate, and mixtures thereof. In certainembodiments, the dextran polymer derivative is selected from the groupconsisting of dextran acetate succinate, dextran propionate succinate,dextran acetate propionate succinate, and mixtures thereof.

In one embodiment, a dosage form comprises a composition comprising from0.01 to 99 wt % of an active agent and from 1 to 99.99 wt % of a dextranpolymer derivative. The dextran polymer derivative is selected from thegroup consisting of dextran acetate, dextran propionate, dextransuccinate, dextran acetate propionate, dextran acetate succinate,dextran propionate succinate, dextran acetate propionate succinate, andmixtures thereof. At least 50 wt % of the composition comprises theactive agent and dextran polymer derivative. At least 5 wt % of thedosage form comprises the composition.

In one embodiment, a dosage form comprises a composition comprising anactive agent and a dextran polymer derivative, where at least 5 wt % ofthe dosage form is comprised of the active agent and dextran polymerderivative. In another embodiment, at least 10 wt % of the dosage formconsists essentially of the active agent and dextran polymer derivative.In another embodiment, at least 20 wt % of the dosage form consistsessentially of the active agent and dextran polymer derivative. Inanother embodiment, at least 25 wt % of the dosage form consistsessentially of the active agent and dextran polymer derivative.

In still another embodiment, the invention provides a method of treatingan animal in need of therapy comprising administering an embodiment ofthe composition to an animal via a mode selected from oral, buccal,mucosal, sublingual, intravenous, intra-arterial, intramuscular,subcutaneous, intraperitoneal, intraarticular, infusion, intrathecal,intraurethral, topical, subdermal, transdermal, intranasal, inhalation,pulmonary tract, intratracheal, intraocular, ocular, intraaural,vaginal, and rectal. In certain embodiments, the composition isadministered to an animal via a mode selected from the group consistingof oral, buccal, mucosal, sublingual, intravenous, intra-arterial,intramuscular, subcutaneous, intraperitoneal, intraarticular, infusion,intrathecal, intraurethral, topical, subdermal, transdermal, intranasal,inhalation, pulmonary tract, intratracheal, intraocular, ocular,intraaural, vaginal, and rectal.

The invention provides one or more of the following advantages. Thedextran polymer derivatives have a combination of substituent degrees ofsubstitution tailored to provide utility for pharmaceuticalcompositions.

When used to form combinations of active agents, such polymers provideenhanced concentrations of dissolved active agent in a use environment.When used in combination with active agents that are prone to rapidcrystallization from supersaturated aqueous solutions, such polymers areparticularly effective at sustaining high concentrations of the activeagent and thereby enhancing absorption of active agent in vivo.

When the compositions are dosed parenterally, the compositions of thepresent invention have the advantage of being at least biocompatible orwell tolerated and often have the advantage of being biodegradable.

The foregoing and other objectives, features, and advantages of theinvention will be more readily understood upon consideration of thefollowing detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a figure showing the results of powder X-ray diffraction of asample of the dispersion of Example 1.

DETAILED DESCRIPTION

Pharmaceutical compositions are provided comprising an active agent anda dextran polymer derivative. Dextran polymer derivatives, activeagents, suitable compositions and methods for making them, and suitablemethods for delivering the compositions to a patient in need of therapyare described in detail below.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, percentages, and soforth, as used in the specification or claims are to be understood asbeing modified by the term “about.” Accordingly, unless otherwiseindicated, implicitly or explicitly, the numerical parameters set forthare approximations that may depend on the desired properties soughtand/or limits of detection under standard test conditions/methods. Whendirectly and explicitly distinguishing embodiments from discussed priorart, the embodiment numbers are not approximates unless the word “about”is recited.

Dextran Polymer Derivatives

Dextran polymer derivatives are polymers formed by the derivatization ofdextran with ester-linked groups. The groups ester-linked to the dextranmay be acetate, propionate, succinate, or any combination of the threegroups. Dextran is an α-D-1,6-glucose-linked glucan. It may haveside-chains linked to the backbone of the dextran polymer, with thedegree of branching being approximately 5%, and the branches beingmostly 1-2 glucose units long. A fragment of the dextran structure isillustrated below.

The term “dextran polymer derivative” refers to any of the family ofdextran polymers that have acetate, propionate, and/or succinate groupsattached via ester linkages to a significant fraction of the dextranpolymer's hydroxyl groups.

In one embodiment, the dextran polymer derivative is selected from thegroup consisting of dextran acetate, dextran propionate, dextransuccinate, dextran acetate propionate, dextran acetate succinate,dextran propionate succinate, dextran acetate propionate succinate, andmixtures thereof. In another embodiment, the dextran polymer derivativeis dextran acetate succinate. In yet another embodiment, the dextranpolymer derivative is dextran propionate succinate.

For example, a fragment of dextran propionate succinate is illustratedbelow.

The degree of substitution of each substituent is chosen so that theactive agent combined with the dextran polymer derivative will besuitable for the intended formulation. “Degree of substitution” or “DS”refers to the average number of the three hydroxyls per sacchariderepeat unit on the dextran chain that have been substituted. Forexample, if all of the hydroxyls on the dextran chain have beensubstituted by acetate groups, the degree of substitution of acetategroups is 3. In the structure of dextran propionate succinate shownabove, the degree of substitution of propionate groups is 2, while thedegree of substitution of succinate groups is 0.33.

In one embodiment, the degree of substitution of the acetate,propionate, and succinate groups are such that when adding the totaldegree of substitution of acetate, propionate and succinate, the totaldegree of substitution is greater than or equal to 0.05. In anotherembodiment, the total degree of substitution is greater than or equal to0.15. In another embodiment, the total degree of substitution is greaterthan or equal to 0.25. In still another embodiment, the total degree ofsubstitution is greater than or equal to 0.50. In yet anotherembodiment, the total degree of substitution is greater than or equal to0.75.

In one embodiment, the dextran polymer derivative is dextran acetate,wherein the degree of substitution for acetate groups ranges from 0.05to 3.0. In another embodiment, the dextran polymer derivative is dextranacetate, wherein the degree of substitution for acetate groups rangesfrom 0.05 to 2.0. In another embodiment, the dextran polymer derivativeis dextran acetate, wherein the degree of substitution for acetategroups ranges from 0.25 to 1.8. In another embodiment, the dextranpolymer derivative is dextran acetate, wherein the degree ofsubstitution for acetate groups is greater than 1.0.

In still another embodiment, the dextran polymer derivative is dextranpropionate, wherein the degree of substitution for propionate groupsranges from 0.05 to 3.0. In another embodiment, the dextran polymerderivative is dextran propionate, wherein the degree of substitution forpropionate groups ranges from 0.05 to 2.0. In another embodiment, thedextran polymer derivative is dextran propionate, wherein the degree ofsubstitution for propionate groups ranges from 0.25 to 2.0. In anotherembodiment, the dextran polymer derivative is dextran propionate,wherein the degree of substitution for propionate groups ranges from 0.5to 2.0. In another embodiment, the dextran polymer derivative is dextranpropionate, wherein the degree of substitution for propionate groups isgreater than 1.0.

In still another embodiment, the dextran polymer derivative is dextransuccinate, wherein the degree of substitution for succinate groupsranges from 0.05 to 3.0. In another embodiment, the dextran polymerderivative is dextran succinate, wherein the degree of substitution forsuccinate groups ranges from 0.05 to 2.8. In another embodiment, thedextran polymer derivative is dextran succinate, wherein the degree ofsubstitution for succinate groups ranges from 0.5 to 2.5.

In another embodiment, the dextran polymer derivative is dextran acetatepropionate, wherein the degree of substitution for acetate groups rangesfrom 0.05 to 2.5, and the degree of substitution for propionate groupsranges from 0.05 to 2.5. In another embodiment, the dextran polymerderivative is dextran acetate propionate, wherein the degree ofsubstitution for acetate groups ranges from 0.1 to 2.0, and the degreeof substitution for propionate groups ranges from 0.1 to 2.0.

In another embodiment, the dextran polymer derivative is dextran acetatesuccinate, wherein the degree of substitution for acetate groups rangesfrom 0.25 to 2.5, and the degree of substitution for succinate groupsranges from 0.05 to 1.5. In another embodiment, the dextran polymerderivative is dextran acetate succinate, wherein the degree ofsubstitution for acetate groups ranges from 0.5 to 2.5, and the degreeof substitution for succinate groups ranges from 0.05 to 1.5. In stillanother embodiment, the dextran polymer derivative is dextran acetatesuccinate, wherein the degree of substitution for acetate groups rangesfrom 1.0 to 2.3, and the degree of substitution for succinate groupsranges from 0.1 to 1.5.

In another embodiment, the dextran polymer derivative is dextranpropionate succinate, wherein the degree of substitution for propionategroups ranges from 0.1 to 2.5, and the degree of substitution forsuccinate groups ranges from 0.05 to 1.5. In another embodiment, thedextran polymer derivative is dextran propionate succinate, wherein thedegree of substitution for propionate groups ranges from 0.25 to 2.0,and the degree of substitution for succinate groups ranges from 0.1 to1.5.

In another embodiment, the dextran polymer derivative is dextran acetatepropionate succinate, wherein the degree of substitution for acetategroups ranges from 0.05 to 2.5, the degree of substitution forpropionate groups ranges from 0.05 to 2.5, and the degree ofsubstitution for succinate groups ranges from 0.05 to 1.5. In anotherembodiment, the dextran polymer derivative is dextran acetate propionatesuccinate, wherein the degree of substitution for acetate groups rangesfrom 0.1 to 2.0, the degree of substitution for propionate groups rangesfrom 0.1 to 2.0, and the degree of substitution for succinate groupsranges from 0.1 to 1.5.

In one embodiment, the dextran polymer derivative has a degree ofsubstitution of succinate that is 0.05 or more. A degree of substitutionof succinate groups of 0.05 or more is desirable as this imparts anegative charge to the polymer at physiologically relevant pH ranges (pH1-8). When making nanoparticles comprising the active agent and adextran polymer derivative with a DS_(succinate)≧0.05, this chargeserves to stabilize the nanoparticles, minimizing or avoidingaggregation. For solid dispersions, the succinate groups, combined withthe acetate and/or propionate groups, yields stable. Finally, thepresence of succinate groups allows the dextran polymer derivative to berelatively hydrophobic in its protonated form for dissolution in organicsolvents; for physical stability, resulting in low water absorption; andfor compatibility with hydrophobic active agents. In one embodiment, adextran polymer derivative with a DS_(succinate)≧0.05 is water solubleor dispersible when ionized, as it is in pH environments above about pH5 (e.g., in vivo).

In one embodiment, the dextran used to form the dextran polymerderivative has a molecular weight that may range from 1,000 to 200,000daltons. As used herein, by “molecular weight” is meant thenumber-average molecular weight as determined by chromatographic methodswell known in the art. In these methods, the number-average molecularweight corresponds to the arithmetic mean of the molecular weights ofindividual macromolecules. In one embodiment, the dextran used to formthe dextran polymer derivative has a molecular weight of from 1,000 to200,000 daltons. In another embodiment, the dextran used to form thedextran polymer derivative has a molecular weight of from 2,000 to70,000 daltons. In still another embodiment, the dextran used to formthe dextran polymer derivative has a molecular weight of from 2,000 to25,000 daltons.

Thus, in one embodiment, the dextran polymer derivative has a molecularweight of from 1,000 to 200,000 daltons. In another embodiment, thedextran polymer derivative has a molecular weight ranging from 3,000daltons to 100,000 daltons. In another embodiment, the dextran polymerderivative has a molecular weight of from 3,000 to 70,000 daltons. Instill another embodiment, the dextran polymer derivative has a molecularweight of from 2,000 to 25,000 daltons.

The degree of substitution of the substituents may be chosen such thatthe polymer has the desired physical properties. In one embodiment, thedegree of substitution is adjusted to obtain a dextran polymerderivative with the desired aqueous solubility or dispersability. A testto determine the aqueous solubility of a dextran polymer derivative maybe performed as follows. The dextran polymer derivative is initiallypresent in bulk powder form with an average particle size of greaterthan about 1 micron. The polymer alone is administered at aconcentration of 0.2 mg/mL to a buffer solution at the desired pH andstirred for approximately 1 hour at room temperature. Next, a nylon 0.45μm filter is weighed, and the solution is filtered. The filter is thendried overnight at 40° C., and weighed the next day. The aqueoussolubility of the polymer is calculated from the amount of polymer addedto the buffer solution minus the amount of polymer remaining on thefilter.

Similar procedures can be used to determine the effect of pH on theaqueous solubility of the dextran polymer derivatives. In this case theprocedures are performed using aqueous buffer solutions with various pHvalues.

In one embodiment, the dextran polymer derivative is aqueous soluble. By“aqueous soluble” is meant that the dextran polymer derivative has anaqueous solubility of at least 1 mg/mL over at least a portion of thephysiologically relevant pH range of 1-8. When the dextran polymerderivative is dextran acetate, the DS_(acetate) should be less thanabout 1.5. When the dextran polymer derivative is dextran propionate,the DS_(propionate) should be less than about 1.3. When the dextranpolymer derivative is dextran acetate propionate, the combined degree ofsubstitution of acetate and propionate should be less than about 1.5,with the combined degree of substitution lower as the percentage ofpropionate relative to acetate increases. When the dextran polymerderivative also includes a DS_(succinate) of ≧0.05, somewhat higherdegrees of substitution of acetate and propionate can be tolerated withthe polymer being aqueous soluble. Generally, increasing the degree ofsubstitution of succinate also promotes solubility of the dextranpolymer derivative at pH values above about 5.0.

In another embodiment, the degree of substitution on the dextran polymerderivative is chosen so that the dextran polymer derivative is anenteric polymer. By “enteric polymer” is meant that the polymer has anaqueous solubility of less than 0.1 mg/mL at a pH of about 3.0 or less,and an aqueous solubility of at least 1 mg/mL at a pH of greater thanabout 7. The actual pH above which it is desired for the dextran polymerderivative to become aqueous soluble will depend on the application andcan be varied by adjusting the ratio of the acetate plus propionategroups to the succinate groups. The pH value where the polymer becomessoluble will generally increase from about 3 to about 7 as the ratio ofacetate plus propionate groups to succinate groups increases.

In still another embodiment, the degree of substitution on the dextranpolymer derivative is chosen so that the dextran polymer derivative ispoorly aqueous soluble. By “poorly aqueous soluble” is meant that thepolymer has a solubility of less than 0.1 mg/mL over at least a portionof the physiologically relevant pH range of 1-8. Generally, for adextran polymer derivative to be poorly aqueous soluble, the combineddegree of substitution of acetate and propionate is high (greater thanabout 1), while the degree of substitution of succinate is low (lessthan about 0.1).

The degree of substitution of substituents may also be used to formdextran polymer derivatives with other desirable properties, dependingon the formulation desired. For example, in some embodiments, it isdesirable that the absorption of water by the polymer be low, such asfor powders for pulmonary delivery of the composition. A relatively highdegree of substitution of any of the acetate, propionate, or succinategroups or combinations thereof will result in a dextran polymerderivative that absorbs less water from the surrounding atmosphererelative to compositions formed from underivatized dextran. In someembodiments, this leads to increased stability of the active agent inthe composition. In particular, when the composition is a powder, lowabsorption of water can lead to the Tg of the composition being higherand therefore the powder being resistant to agglomeration (e.g., forrespirable particles) and, when the composition is a solid dispersion,the active agent will tend to remain dispersed and not separate from thepolymer as amorphous or crystalline active agent domains.

Thus, in one embodiment, the degree of substitution of acetate,propionate, and succinate are chosen such that the mass of waterabsorbed by the dextran polymer derivative is significantly less thanthat absorbed by underivatized dextran. In one embodiment, the mass ofwater absorbed by the dextran polymer derivative is at least 10% lessthan that absorbed by underivatized dextran when measured by dynamicvapor absorption at 90% relative humidity (RH) and 25° C. Forcomparison, the mass of water absorbed by underivatized dextran, whenmeasured by dynamic vapor absorption at 90% RH and 25° C. is about 26 wt%. Thus, in one embodiment, the dextran polymer derivative absorbs lessthan 23 wt % water when measured by dynamic vapor absorption at 90% RHat 25° C. In another embodiment, the dextran polymer derivative absorbsless than 20 wt % water at 90% RH at 25° C. In still another embodiment,the dextran polymer derivative absorbs less than 18 wt % water at 90% RHat 25° C.

The addition of ester-linked acetate, propionate, and succinate groupsto the dextran polymer to reduce water absorption also results in theglass-transition temperature (Tg) of the polymer equilibrated with ahumid atmosphere being higher than that of the correspondingunderivatized dextran. This higher Tg is desirable for some compositionscomprising an active agent and dextran polymer derivative, for example,for long-term stability of compositions comprising non-crystallineactive agent.

Thus, in one embodiment, the degree of substitution of acetate,propionate, and succinate is chosen such that the Tg of the dextranpolymer derivative is significantly higher than that of underivatizeddextran when exposed to a humid atmosphere. In one embodiment, the Tg ofthe dextran polymer derivative is at least 10° C. greater than that ofunderivatized dextran when the powders are exposed to a 50% RHatmosphere at 25° C. For comparison, the Tg of underivatized dextranpowder when exposed to a 50% RH atmosphere at 25° C. is about 45 to 50°C. Thus, in one embodiment, the Tg of the dextran polymer derivative isat least 50° C. when exposed to a 50% RH atmosphere at 25° C. In anotherembodiment, Tg of the dextran polymer derivative is at least 60° C. whenexposed to a 50% RH atmosphere at 25° C.

In one embodiment, the dextran polymer derivative is biocompatible. By“biocompatible” is meant that for some delivery routes, the polymer iscompatible with and has no significant toxic effect on the livingorganism to which it is administered. In one embodiment, the polymerdoes not significantly elicit humoral or cell-based immune responseswhen administered in vivo.

In yet another embodiment, the dextran polymer derivative isbiodegradable. By “biodegradable” is meant that the polymer will degradewhen administered in vivo. By “degrade” is meant that in an in vivo useenvironment, the polymer is broken down into smaller species that can beabsorbed, metabolized, or otherwise eliminated or “cleared” from the useenvironment. This degradation can occur through enzymatic, hydrolytic,oxidative, or other reaction, as is well known in the art. The polymermay also degrade into aqueous soluble species that can be cleared fromthe in vivo use environment. For example, the degradation products maybe renally cleared through the kidneys or may enter the lymphatic systemand then exit through the gastro-intestinal tract.

Synthesis of Dextran Polymer Derivatives

Methods for preparation of ester derivatives of carbohydrates are known.See for example Advances in Polymer Science, 205, Polysaccharides II,Edited by Dieter Klemm (Springer-Verlag, Berlin Heidelberg, 2006).Methods for the preparation of the dextran polymer derivatives of thepresent invention can be derived from such known methods. Specifically,the dextran polymer derivatives can be prepared as follows. In a firstmethod, dextran is first modified by substitution with an alkyl groupfollowed by addition of succinate. The dextran is first dissolved in asuitable solvent system such as formamide, dimethyl formamide (DMF), orN-methylpyrrolidone (NMP), together with a base, such as pyridine or thesodium salt of the carboxylate corresponding to the alkyl group to besubstituted. An anhydride of the alkyl group to be substituted onto thedextran backbone is then added to the mixture. The reaction mixture isthen stirred at temperatures ranging from 0 to 100° C. for a period offrom about 30 minutes to 72 hours. When the resulting dextran polymerderivative is poorly aqueous soluble, the reaction can then be quenchedby adding water to precipitate the polymer. The resulting precipitatecan be collected by filtration. Alternatively, the polymer can beisolated by extraction into a solvent, such as ethyl acetate ormethylene chloride, and the extraction solvent removed, for example, byevaporation or spray drying. The polymer can be further rinsed, filteredand dried prior to use.

The resulting dextran polymer derivative is then dissolved in thecarboxylic acid corresponding to the alkyl group that has beensubstituted together with the sodium salt of the correspondingcarboxylate. For example, if dextran propionate has been prepared, thenit is dissolved in propionic acid together with sodium propionate.Succinic anhydride is then added. The reaction mixture may then bestirred at temperatures ranging from 0 to 100° C. for a period of fromabout 30 minutes to 72 hours. The reaction may then be quenched byadding water to precipitate the polymer. The resulting precipitate maybe collected by filtration. Alternatively, the polymer may be isolatedby extraction into a solvent, such as ethyl acetate or methylenechloride, and the extraction solvent removed, for example, byevaporation or spray drying. The polymer may be further rinsed, filteredand dried prior to use.

In another method, dextran is first modified by substitution with analkyl group followed by addition of succinate, but the dextran alkylester is not isolated and purified prior to addition of the succinicanhydride. In this method, the dextran alkyl ester is first formed,followed by addition of succinic anhydride.

In yet another method, the dextran is modified by substitution with analkyl group and succinate simultaneously. In this method, dextran may befirst dissolved in a suitable solvent system such as formamide, DMF, orNMP, together with the sodium salt of the carboxylate corresponding tothe alkyl group to be substituted. An anhydride of the alkyl group to besubstituted onto the dextran backbone and succinic anhydride may then beadded to the mixture. The reaction mixture may then be stirred attemperatures ranging from 0 to 100° C. for a period of from about 30minutes to 72 hours. The reaction may then be quenched by adding waterto precipitate the polymer. The resulting precipitate may be collectedby filtration. Alternatively, the polymer may be isolated by extractioninto a solvent, such as ethyl acetate or methylene chloride, and theextraction solvent removed, for example, by evaporation or spray drying.The polymer may be further rinsed, filtered and dried prior to use.

The degree of substitution of alkyl esters and succinate groups on thedextran polymer may be determined using standard techniques, such asnuclear magnetic resonance (NMR) analysis or high-performance liquidchromatography (HPLC). For example, ¹³C NMR analysis may be used todetermine the number of alkyl ester and succinate groups using the ratioof the peak area of the groups to the peak area of the anomeric carbonin the dextran ring.

Active Agents

Compositions containing dextran polymer derivatives are suitable for usewith any biologically active compound desired to be administered to apatient in need of the active agent. The compositions may contain one ormore active agents. As used herein, by “active agent” is meant a drug,medicament, pharmaceutical, therapeutic agent, nutraceutical, or othercompound that may be desired to be administered to the body. The activeagent may be a “small molecule,” generally having a molecular weight ofabout 2000 Daltons or less. The active agent may also be a “biologicalactive agent.” Biological active agents include proteins, antibodies,antibody fragments, peptides, oligoneucleotides, vaccines, and variousderivatives of such materials. In one embodiment, the active agent is asmall molecule. In another embodiment, the active agent is a biologicalactive agent. In still another embodiment, the active agent is a mixtureof a small molecule and a biological active agent.

The active agent may be highly water soluble (i.e., greater than 100mg/mL), sparingly water soluble (i.e., 5-30 mg/mL), or poorly watersoluble (i.e., less than 5 mg/mL). In one embodiment, the active agentis “poorly water soluble,” and the active agent has a solubility inwater (over the pH range of 6.5 to 7.5 at 25° C.) of less than 5 mg/mL.The active agent may have an even lower aqueous solubility, such as lessthan about 1 mg/mL, less than about 0.1 mg/mL, and even less than about0.01 mg/mL.

The active agent should be understood to include the nonionized form ofthe active agent, pharmaceutically acceptable salts of the active agent,or any other pharmaceutically acceptable forms of the active agent. By“pharmaceutically acceptable forms” is meant any pharmaceuticallyacceptable derivative or variation, including stereoisomers,stereoisomer mixtures, enantiomers, solvates, hydrates, isomorphs,polymorphs, pseudomorphs, neutral forms, salt forms and prodrugs.

Examples of classes of active agents include, but are not limited to,compounds for use in the following therapeutic areas: antihypertensives,antianxiety agents, antiarrythmia agents, anticlotting agents,anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, antineoplastics, beta blockers,anti-inflammatories, antipsychotic agents, cognitive enhancers,anti-atherosclerotic agents, cholesterol-reducing agents,triglyceride-reducing agents, antiobesity agents, autoimmune disorderagents, anti-impotence agents, antibacterial and antifungal agents,hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's diseaseagents, antibiotics, anti-angiogenesis agents, anti-glaucoma agents,anti-depressants, bronchodilators, glucocorticoids, steroids, andantiviral agents.

Compositions Comprising Active Agent and Dextran Polymer Derivatives

The compositions of the present invention comprise an active agent and adextran polymer derivative. In one embodiment, the compositions are inthe form of a plurality of particles. In one embodiment, each of theparticles comprises the active agent and the dextran polymer derivative.As used herein, the term “particles” means a small piece of matterhaving a characteristic diameter of less than about 3000 μm. In anotherembodiment, the particles are granulated into granules using standardmethods known in the art, such as dry granulation, wet granulation, highshear granulation, and the like.

In another embodiment, the composition is in the form of a layer orcoating on a substrate. The coating may be formed by spray coating,powder coating, press coating, and other methods known in the art. Inthis embodiment, the composition is distinct from and separate from thesubstrate onto which the composition is coated.

In one embodiment, the active agent and dextran polymer derivativeconstitute at least 50 wt % of the composition. In another embodiment,the active agent and dextran polymer derivative constitute at least 75wt % of the composition.

In still another embodiment, the active agent and dextran polymerderivative constitute at least 90 wt % of the composition. In yetanother embodiment, the composition consists essentially of the activeagent and the dextran polymer derivative.

In one embodiment, compositions are in the form selected from the groupconsisting of (1) a solid dispersions, (2) nanoparticles, (3)microparticles (i.e., particles having a characteristic diameter ofgreater than about 400 nm), (4) solid materials for reconstitution assuspensions, and (5) solid materials where multiple small crystalline orsemi-crystalline or amorphous active agent domains are dispersed inlarger particles or solid objects comprising the dextran polymerderivative. These embodiments are discussed herein below.

Solid Dispersions

In one embodiment, the composition is in the form of a solid dispersioncomprising the active agent and the dextran polymer derivative, whereinat least 90 wt % of the active agent in the dispersion isnon-crystalline. In one embodiment, the dextran polymer derivative maybe aqueous soluble, enteric, or poorly aqueous soluble. In anotherembodiment, the dextran polymer derivative is aqueous soluble orenteric.

The relative amounts of active agent and dextran polymer derivative inthe dispersion may range from 0.01 wt % to 99 wt % active agent, andfrom 1 wt % to 99.99 wt % dextran polymer derivative. In otherembodiments, the amount of active agent may range from 0.1 wt % to 80 wt%, or from 0.1 to 60 wt %, or from 1 to 40 wt %. The amount of dextranpolymer derivative may range from 20 wt % to 99.9 wt %, 40 wt % to 99.9wt % or from 60 wt % to 99 wt %. In still another embodiment, thedispersions have the following composition: from 0.1 to 80 wt % activeagent, and from 20 to 99.9 wt % dextran polymer derivative. In yetanother embodiment, the dispersions have the following composition: from0.1 to 60 wt % active agent, and from 40 to 99.9 wt % dextran polymerderivative. In another embodiment, the dispersions have the followingcomposition: from 1 to 40 wt % active agent, and from 60 to 99 wt %dextran polymer derivative.

In one embodiment, at least 90 wt % of the active agent present in thedispersion is amorphous. By “amorphous” is meant that the active agentis non-crystalline as determined by differential scanning calorimetry,powder X-ray diffraction (PXRD), by solid state nuclear magneticresonance (NMR), or by any other known quantitative measurement.

As the dextran polymer derivative is amorphous, the dispersion maycomprise one or more active agent-rich domains dispersed in a dextranpolymer derivative phase, or the dispersion may comprise a “solidsolution” of active agent molecules dispersed in the dextran polymerderivative, or the dispersions may comprise any state or combination ofstates in between. The term “solid solution” includes boththermodynamically stable solid solutions in which the active agent iscompletely dissolved in the polymer, as well as homogeneous materialsconsisting of amorphous active agent molecularly dispersed throughoutthe polymer in amounts greater than the solubility of the active agentin the polymer. A dispersion is considered a “solid solution” when itdisplays a single Tg when analyzed by differential scanning calorimetry.In one embodiment, the dispersions have at least one Tg due to theamorphous character of the polymer. In another embodiment, essentiallyall of the active agent and the dextran polymer derivative in thedispersion are in the form of a solid solution. Thus, in one embodiment,the composition consists essentially of a solid solution of the activeagent and the dextran polymer derivative.

In another embodiment, the dispersion comprises two or more activeagents.

In still another embodiment, the relative amounts of active agent andpolymer are chosen so that the dispersions have a glass transitiontemperature of at least 50° C. at 50% relative humidity. In anotherembodiment, when evaluated at a relative humidity of less than 5%, thedispersions have a glass transition temperature of at least 50° C., oreven at least 80° C., or even at least 100° C. The solid dispersion hasa single glass transition temperature, indicating that the soliddispersion is a homogeneous solid solution.

The solid dispersions of the present invention may be formed by anymethod known in the art, including milling, extrusion, precipitation, orsolvent addition followed by solvent removal. For example, active agentand the dextran polymer derivative may be processed by heat, mechanicalmixing and extrusion using, for example, a twin-screw extruder. Theproduct may then be milled to the desired particle size. In anotherexample, the active agent and dextran polymer derivative are dissolvedin a solvent in which both materials are soluble. The dispersions maythen be formed from the solution by any known process, includingprecipitation in a miscible non-solvent, emulsifying in an immisciblenon-solvent, or by forming droplets followed by removal of the solventby evaporation.

In one embodiment, the solid dispersion is formed by spray drying. Theactive agent, the dextran polymer derivative, and optional excipientsmay be dissolved in a solvent. Thus, the fluid that is spray dried maybe a suspension or a homogeneous solution or a combination of dissolvedand suspended materials. In one embodiment, the fluid that is spraydried comprises a homogeneous solution of active agent and dextranpolymer derivative dissolved together in a solvent. In anotherembodiment, the fluid that is spray dried consists essentially of asolution of active agent and dextran polymer derivative dissolved in asolvent. In still another embodiment, the fluid that is spray driedcomprises a suspension of active agent particles in a solution ofdextran polymer derivative dissolved in a solvent.

The solvent may be any solvent or mixture of solvents capable ofdissolving both the active agent and polymer having a boiling point ofless than about 150° C. Suitable solvents include water, acetone,methanol, ethanol, methyl acetate, ethyl acetate, tetrahydrofuran (THF),dichloromethane and mixtures of solvents. When the spray drying solutioncomprises an organic solvent that is water miscible, such as acetone ormethanol, water may be added to the solution. The spray drying solutionis then sprayed through an atomizer such as a pressure nozzle or twofluid nozzle into a spray drying chamber. The droplets are contactedwith a heated drying gas such as dry nitrogen. Droplets dry rapidly,forming particles of the solid amorphous dispersion comprising theactive agent and dextran polymer derivative. The particles exit thespray dryer and are collected, such as in a cyclone.

In one embodiment, the solid dispersion is formed in the presence of ahigh surface area substrate. Exemplary high surface area substratesinclude inorganic oxides, such as SiO₂ (fumed silica), TiO₂, ZnO₂, ZnO,Al₂O₃, zeolites, and inorganic molecular sieves; water insolublepolymers, such as cross-linked cellulose acetate phthalate, cross-linkedhydroxypropyl methyl cellulose acetate succinate, cross-linked polyvinylpyrrolidinone, (also known as cross povidone), cross-linked celluloseacetate phthalate, microcrystalline cellulose, polyethylene/polyvinylalcohol copolymer, polyethylene polyvinyl pyrrolidone copolymer,cross-linked carboxymethyl cellulose, sodium starch glycolate,cross-linked polystyrene divinyl benzene; and activated carbons. In oneembodiment, the substrate is fumed silica. In this embodiment, the soliddispersion may be adsorbed onto the surface of the substrate, coated onthe outside of the substrate, or any combination of these.

In another embodiment, the solid dispersion may be formed as a coatingon an appropriate substrate. For example, the solid dispersion may becoated onto multiparticulates having diameters ranging from 50 μm to5,000 μm. In another example, the solid dispersion may be coated onto atablet or capsule. In still another embodiment, the solid dispersion maybe formed into a layer that is incorporated into a tablet.

Nanoparticles

In one embodiment, the composition is in the form of nanoparticlescomprising the active agent and the dextran polymer derivative. By“nanoparticles” is meant a plurality of small particles in which theaverage size of the particles is less than about 500 nm. In suspension,by “average size” is meant the effective cumulant diameter as measuredby dynamic light scattering (DLS), using for example, BrookhavenInstruments' 90Plus particle sizing instrument. By “size” is meant thediameter if the particles were spherical particles, or the maximumdiameter for non-spherical particles. In some embodiments, the averagesize of the nanoparticles is less than 400 nm, less 300 nm, less than200 nm, and even less than 150 nm. In one embodiment, the average sizeof the nanoparticles is less than 150 nm. In another embodiment, theaverage size of the nanoparticles is less than 100 nm. In still anotherembodiment, the average size of the nanoparticles is less than 75 nm. Inyet another embodiment, the average size of the nanoparticles is lessthan 50 nm. In another embodiment, the nanoparticles range in size from1 nm to 400 nm, from 1 nm to 300 nm, from 1 nm to 200 nm, from 10 nm to400 nm, or from 30 nm to 400 nm.

The width of the particle size distribution in suspension is given bythe “polydispersity” of the particles, which is defined as the relativevariance in the correlation decay rate distribution, as is known by oneskilled in the art. See B. J. Fisken, “Revisiting the method ofcumulants for the analysis of dynamic light-scattering data,” AppliedOptics, 40(24), 4087-4091 (2001) for a discussion of cumulant diameterand polydispersity. In one embodiment, the polydispersity of thenanoparticles is less than 0.5. In another embodiment, thepolydispersity of the nanoparticles is less than about 0.3. In oneembodiment, the average size of the nanoparticles is less than 500 nmwith a polydispersity of 0.5 or less. In another embodiment, the averagesize of the nanoparticles is less than 300 nm with a polydispersity of0.5 or less. In still another embodiment, the average size of thenanoparticles is less than 200 nm with a polydispersity of 0.5 or less.In yet another embodiment, the average size of the nanoparticles is lessthan 200 nm with a polydispersity of 0.3 or less.

When the composition is in the form of a nanoparticle, the nanoparticlescomprising active agent and the dextran polymer derivative, along withother optional excipients that the nanoparticles may be suspended in anaqueous solution without substantially dissolving. In one embodiment, anaqueous solution may be added to a dried form of the nanoparticles toform a concentration suspension for delivery to a use environment suchas by injection, subcutaneously or intravascularly. In such cases, thenanoparticles may dissolve upon dilution into the use environment, oralternatively, they may be sufficiently insoluble to remain undissolvedfor many days. In one embodiment, the dextran polymer derivative may beenteric or poorly aqueous soluble. Thus, in one embodiment, the dextranpolymer derivative is enteric. In another embodiment, the dextranpolymer derivative is poorly aqueous soluble.

The nanoparticles can exist in a number of different configurations. Inone embodiment, the nanoparticles comprise a core, the core comprisingthe active agent and the dextran polymer derivative. As used herein, theterm “core” refers to the interior portion of the nanoparticle. Thenanoparticles also have a “surface portion,” meaning the outside orexterior portion of the nanoparticle. Thus, the nanoparticles consist ofa core (i.e., the interior portion) and a surface portion. In someembodiments, described herein below, materials may be adsorbed to thesurface portion of the nanoparticle. Materials adsorbed to the surfaceportion of the nanoparticle are considered part of the nanoparticle, butare distinguishable from the core of the nanoparticle. Methods todistinguish materials present in the core versus materials adsorbed tothe surface portion of the nanoparticle include (1) thermal methods,such as differential scanning calorimetry (DSC); (2) spectroscopicmethods, such as X-ray photoelectron spectroscopy (XPS), transmissionelectron microscopy (TEM) with energy dispersive X-ray (EDX) analysis,Fourier transform infra red (FTIR) analysis, and Raman spectroscopy; (3)chromatographic techniques, such as high performance liquidchromatography (HPLC), and gel-permeation chromatography (GPC); and (4)other techniques known in the art.

The active agent present in the core can exist in pure active agentdomains (crystalline or non-crystalline), as a thermodynamically stablesolid solution of non-crystalline active agent distributed throughoutthe dextran polymer derivative, as a supersaturated solid solution ofnon-crystalline active agent distributed throughout the dextran polymerderivative, or any combination of these states or those states that liebetween them. When the glass-transition temperature (Tg) of thenon-crystalline active agent is different from the Tg of the purepolymer by at least about 20° C., the core may exhibit a Tg that isdifferent from the Tg of pure non-crystalline active agent or purepolymer. In one embodiment, less than 20 wt % of the active agent ispresent in non-crystalline active agent domains, with the remainingactive agent distributed throughout the polymer.

In one embodiment, the nanoparticles are homogeneous, meaning that thecomposition on the surface of the nanoparticle is essentially the sameas in the core of the nanoparticle. In such cases, the nanoparticles maycomprise, in one embodiment, a solid amorphous dispersion of the typedescribed in the previous section, except for the small size—less than400 nm. In another embodiment, the active agent is present as one ormore amorphous or crystalline domains throughout each nanoparticle.

In still another embodiment, the core comprises the active agent and thedextran polymer derivative, with a surface stabilizer adsorbed to thesurface portion of the nanoparticle.

In one embodiment, at least 50 wt % of the active agent in thenanoparticles is crystalline. In another embodiment, at least 75 wt % ofthe active agent in the nanoparticles is crystalline.

In still another embodiment, at least 90 wt % of the active agent in thenanoparticles is non-crystalline. In another embodiment, at least about95 wt % of the active agent in the nanoparticle is non-crystalline; inother words, the amount of active agent in crystalline form does notexceed about 5 wt %.

Amounts of crystalline active agent may be measured by Powder X-RayDiffraction (PXRD), by Differential Scanning Calorimetry (DSC), by solidstate nuclear magnetic resonance (NMR), or by any other knownquantitative measurement.

The active agent and polymer are collectively present in thenanoparticle in an amount ranging from about 50 wt % to 100 wt %. In oneembodiment, the active agent and polymer collectively may constitute atleast 60 wt %, or even at least 80 wt % of the nanoparticle. In anotherembodiment, the nanoparticles consist essentially of the active agentand the dextran polymer derivative. By “consist essentially of is meantthat the nanoparticle contains less than 1 wt % of any other excipientsand that any such excipients have substantially no effect on theperformance or properties of the nanoparticle.

The amount of active agent in the nanoparticle may range from 0.01 wt %to 99 wt %. In one embodiment, the amount of active agent in thenanoparticle ranges from 0.1 wt % to 80 wt %, or from 0.1 to 60 wt %, orfrom 1 to 40 wt %. In still another embodiment, the amount of activeagent in the nanoparticle ranges from about 5 wt % to about 75 wt %,from about 5 wt % to about 60 wt %, or from about 5 wt % to about 50 wt%.

To minimize the total mass of the formulation, high active agentloadings are desired. However, if the amount of active agent in thenanoparticle is too high, the nanoparticles suspension becomes unstable,resulting in crystallization of the active agent in the suspension.Additionally, high amounts of active agent in the nanoparticle can leadto crystalline active agent formation when the nanoparticles areisolated from suspension in solid form. Thus, in one embodiment, theamount of active agent in the nanoparticle may be less than about 90 wt%, less than about 80 wt %, or even less than about 75 wt % the totalmass of the nanoparticle.

The amount of dextran polymer derivative may range from 1 wt % to 99.99wt %. The physical stability of the active agent in the nanoparticletends to improve with increasing amounts of the dextran polymerderivative. Accordingly, in one embodiment, the amount of polymer in thenanoparticle is at least 5 wt %, at least 15 wt %, at least 20 wt %, orat least 25 wt %. However, too much polymer will lead to low activeagent loading in the nanoparticle. Thus, in one embodiment, the amountof polymer in the nanoparticle is 80% or less.

The mass ratio of active agent to dextran polymer derivative in thenanoparticle can range from about 1:999 to about 9:1 (that is, fromabout 0.1 wt % active agent to 90 wt % active agent relative to thetotal mass of active agent and dextran polymer derivative in thenanoparticle). In one embodiment, the mass ratio of active agent todextran polymer derivative ranges from about 1:99 to about 4:1 (that is,from about 1 wt % to about 80 wt % active agent relative to the totalmass of active agent and dextran polymer derivative), from about 1:19 toabout 3:1 (that is, from about 5 wt % to about 75 wt %), from about 1:10to about 1:5 (that is, from about 9 wt % to about 60 wt % active agentrelative to the total mass of active agent and dextran polymerderivative in the nanoparticle). In one embodiment, the mass ratio ofactive agent to dextran polymer derivative is less than 9:1, less than4:1, less than 3:1, or even less than 3:2. In other embodiments, themass ratio of active agent to dextran polymer derivative is at least1:999, at least 1:99, and even at least 1:10.

The nanoparticles may optionally comprise a surface stabilizer inaddition to the active agent and the dextran polymer derivative. Thepurpose of the surface stabilizer is to reduce or prevent aggregation orflocculation of the nanoparticles in an aqueous suspension, resulting innanoparticles with improved stability. In one embodiment, the surfacestabilizer is used to stabilize the nanoparticles during the formationprocess. The stabilizer should be inert, in the sense that it does notchemically react with the active agent in an adverse manner, and shouldbe pharmaceutically acceptable.

The surface stabilizer may be distributed throughout the nanoparticle,it may be in higher concentration on the surface of the nanoparticle, orany combination of these. In one embodiment, the surface stabilizer isdistributed throughout the nanoparticle. In another embodiment, thesurface stabilizer is at a higher concentration on the surface of thenanoparticle. When the surface stabilizer is at a higher concentrationon the surface of the nanoparticle, the surface stabilizer may comprisethe outer portion of the nanoparticle, while the dextran polymerderivative may be present in the core of the nanoparticle.

When an optional surface stabilizer is present, it may constitute from0.1 wt % to about 50 wt % of the total mass of the nanoparticles.Generally, lower concentrations of surface stabilizer are desired. Thus,in one embodiment, the surface stabilizer constitutes about 40 wt % orless, or even about 30 wt % or less of the total mass of thenanoparticles.

In one embodiment, the surface stabilizer is an amphiphilic compound,meaning that it has both hydrophobic and hydrophilic regions. In anotherembodiment, the surface stabilizer is a surfactant, including anionic,cationic, zwitterionic, and non-ionic surfactants. Mixtures of surfacestabilizers may also be used.

In one embodiment, the surface stabilizer is a dextran polymerderivative. When the surface stabilizer is a dextran polymer derivative,it may be the same or different than the dextran polymer derivativepresent in the core of the nanoparticle. In one embodiment, an aqueoussoluble dextran polymer derivative is used as the surface stabilizer.

Exemplary surface stabilizers include dextran polymer derivatives,casein, caseinates, dextran, polyvinyl pyrrolidone (PVP),polyoxyethylene alkyl ethers, polyoxyethylene stearates, polyoxyethylenecastor oil derivatives, poly(ethylene oxide-propylene oxide) (also knownas poloxamers), tragacanth, gelatin, polyethylene glycol, bile salts(such as salts of dihydroxy cholic acids, including sodium and potassiumsalts of cholic acid, glycocholic acid, and taurocholic acid),phospholipids (such as phosphatidyl cholines, including1,2-diacylphosphatidylcholine also referred to as PPC or lecithin),sodium dodecylsulfate (also known as sodium lauryl sulfate),benzalkonium chloride, sorbitan esters, polyoxyethylene alkyl ethers,polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fattyacid esters (polysorbates), polyoxyethylene stearates, triethanolamine,sodium docusate, sodium stearyl fumarate, sodium cyclamate, and mixturesand pharmaceutically acceptable forms thereof.

In one embodiment, the surface stabilizer is a bile salt. The bile saltmay be selected from the group sodium glycocholate and sodiumtaurocholate.

The nanoparticles may be formed by any process that results in formationof nanoparticles comprising active agent and a dextran polymerderivative. The active agent used to form the nanoparticles may be in acrystalline or non-crystalline form, or a mixture thereof.

One process for forming nanoparticles is an emulsification process. Inthis process, the active agent and dextran polymer derivative aredissolved in an organic solvent that is immiscible with an aqueoussolution in which active agent and polymers are poorly soluble, formingan organic solution. Solvents suitable for forming the solution ofdissolved active agent and dextran polymer derivative can be anycompound or mixture of compounds in which the active agent and thepolymer are mutually soluble and which is immiscible with the aqueoussolution. As used herein, the term “immiscible” means that the organicsolvent has a solubility in the aqueous solution of less than about 10wt %, less than about 5 wt %, or even less than about 3 wt %. In oneembodiment, the solvent is also volatile with a boiling point of 150° C.or less. Exemplary organic solvents include methylene chloride,trichloroethylene, trichloro-trifluoroethylene, tetrachloroethane,trichloroethane, dichloroethane, dibromoethane, ethyl acetate, phenol,chloroform, toluene, xylene, ethyl-benzene, benzyl alcohol, creosol,methyl-ethyl ketone, methyl-isobutyl ketone, hexane, heptane, ether, andmixtures thereof. In one embodiment, the organic solvents are methylenechloride, ethyl acetate, benzyl alcohol, and mixtures thereof.

In one embodiment, the aqueous solution is water. The optional surfacestabilizer or other components that make up the exterior portion of thenanoparticles may be dissolved in the aqueous solution. When the activeis water soluble, it may be dissolved in the aqueous solution.

Once the organic solution is formed, it is then mixed with the aqueoussolution and homogenized to form an emulsion of fine droplets of thewater immiscible solvent distributed throughout the aqueous phase. Thevolume ratio of organic solution to aqueous solution used in the processwill generally range from 1:100 (organic solution:aqueous solution) to2:3 (organic solution:aqueous solution). In one embodiment, the organicsolution:aqueous solution volume ratio ranges from 1:9 to 1:2 (organicsolution:aqueous solution). The emulsion is generally formed by atwo-step homogenization procedure. The solution of active agent, polymerand organic solvent are first mixed with the aqueous solution using arotor/stator or similar mixer to create a “pre-emulsion”. This mixtureis then further processed with a high-pressure homogenizer that subjectsthe droplets to very high shear, creating a uniform emulsion of verysmall droplets. A portion of the organic solvent is then removed forminga suspension of the nanoparticles in the aqueous solution. Exemplaryprocesses for removing the organic solvent include evaporation,extraction, diafiltration, pervaporation, vapor permeation,distillation, and filtration. In one embodiment, the organic solvent isremoved to a level that is acceptable according to The InternationalCommittee on Harmonization (ICH) guidelines. In another embodiment, theconcentration of organic solvent in the nanoparticle suspension is lessthan the solubility of the organic solvent in the aqueous solution. Evenlower concentrations of organic solvent are often desired. Thus, theconcentration of organic solvent in the nanoparticle suspension may beless than about 5 wt %, less than about 3 wt %, less than 1 wt %, andeven less than 0.1 wt %.

An alternative process to form the nanoparticles is a precipitationprocess. In this process, the dextran polymer derivative is firstdissolved in an organic solvent that is miscible with an aqueoussolution in which the dextran polymer derivative is poorly soluble. Theresulting organic solution is mixed with the aqueous solution causingthe nanoparticles to precipitate. In one embodiment, the active agent isdissolved in the aqueous solution. In another embodiment, the activeagent is dissolved, along with the dextran polymer derivative, in theorganic solution. Solvents suitable for forming the solution ofdissolved active agent and polymer can be any compound or mixture ofcompounds in which the active agent and the polymer are mutually solubleand which is miscible in the aqueous solution. In one embodiment, theorganic solvent is also volatile with a boiling point of 150° C. orless. Exemplary solvents include acetone, methanol, ethanol,tetrahydrofuran (THF), and DMSO. Mixtures of solvents, such as 50%methanol and 50% acetone, can also be used, so long as the active agentand polymer are sufficiently soluble to dissolve the active agent andpolymer. In one embodiment, the solvents are methanol, acetone, andmixtures thereof.

The aqueous solution may be any compound or mixture of compounds inwhich the active agent and polymer are sufficiently insoluble so as toprecipitate to form nanoparticles. In one embodiment, the aqueoussolution is water. In another embodiment, the optional surfacestabilizer is dissolved in the aqueous solution.

The organic solution and aqueous solution are combined under conditionsthat cause solids to precipitate as nanoparticles. The mixing can be byaddition of a bolus or stream of organic solution to a stirringcontainer of the aqueous solution. Alternately a stream or jet oforganic solution can be mixed with a moving stream of aqueous solution.In either case, the precipitation results in the formation of asuspension of nanoparticles in the aqueous solution.

For the precipitation process, the amount of active agent and polymer inthe organic solution depends on the solubility of each in the organicsolvent and the desired ratio of active agent to polymer in theresulting nanoparticles. The organic solution may comprise from about0.1 wt % to about 20 wt % dissolved solids. A dissolved solids contentof from about 0.5 wt % to 10 wt % is usually desired.

The organic solution:aqueous solution volume ratio should be selectedsuch that there is sufficient aqueous solution in the nanoparticlesuspension that the nanoparticles solidify and do not rapidlyagglomerate. However, too much aqueous solution will result in a verydilute suspension of nanoparticles, which may require further processingfor ultimate use. Generally, the organic solution:aqueous solutionvolume ratio should be at least 1:100, but generally should be less than1:2 (organic solution:aqueous solution). In one embodiment, the organicsolution:aqueous solution volume ratio ranges from about 1:20 to about1:3.

Once the nanoparticle suspension is made, a portion of the organicsolvent may be removed from the suspension using methods known in theart. Exemplary processes for removing the organic solvent includeevaporation, extraction, diafiltration, pervaporation, vapor permeation,distillation, and filtration. In one embodiment, the solvent is removedto a level that is acceptable according to ICH guidelines. Thus, theconcentration of solvent in the nanoparticle suspension may be less thanabout 10 wt %, less than about 5 wt %, less than about 3 wt %, less than1 wt %, and even less than 0.1 wt %.

Still another process for forming nanoparticles is through a millingprocess, as is known in the art. One method comprises suspending thecrystalline active agent in a liquid dispersion medium and applyingmechanical means in the presence of grinding media to reduce theparticle size of the active agent substance to the effective averageparticle size. The particles can be reduced in size in the presence of adextran polymer derivative, which acts as a surface modifier.Alternatively, the particles can be contacted with the dextran polymerderivative after attrition.

Resuspending Materials

In another embodiment, the compositions of the present inventioncomprise (a) nanoparticles comprising an active agent, wherein thenanoparticles have an average size of less than 500 nm; and (b) aresuspending material comprising a dextran polymer derivative; whereinthe resuspending material constitutes from 5 wt % to 90 wt % of thecombined mass of (1) the nanoparticles and (2) the resuspendingmaterial.

In one aspect, a dry, solid composition comprises (a) a plurality ofnanoparticles comprising an active agent, and (b) a resuspendingmaterial comprising a dextran polymer derivative, or a pharmaceuticallyacceptable salt form thereof. As used herein, the term “dry, solidpharmaceutical composition” means that the composition is in a solidform and substantially free of liquids.

The solid pharmaceutical composition may take one of manyconfigurations. In one embodiment, at least a portion of thenanoparticles in the solid composition are encapsulated by theresuspending material. By “at least a portion of the nanoparticles areencapsulated by the resuspending material” means that the resuspendingmaterial encapsulates at least a portion of the plurality ofnanoparticles in the composition. The resuspending material mayencapsulate only a portion of the nanoparticles, or may encapsulateessentially all of the nanoparticles in the composition. In oneembodiment, the resuspending material encapsulates essentially all ofthe nanoparticles in the composition.

In one embodiment, the nanoparticles further comprise a poorly aqueoussoluble polymer. In another embodiment, the poorly aqueous solublepolymer is a biocompatible polymer. In yet another embodiment, thepoorly aqueous soluble polymer is a biodegradable polymer. In stillanother embodiment, the poorly aqueous soluble polymer is at least oneof a biocompatible polymer and a biodegradable polymer. Exemplary poorlyaqueous soluble polymers suitable for use in the nanoparticles includedextran polymer derivatives, vinyl polymers and co polymers, such aspoly(vinyl acetate), poly(vinyl acetate-co-vinyl alcohol), andpoly(ethylene-co-vinyl acetate); polylactones, such as poly(lactide),poly(glycolide), poly(mono-hexyl lactide), poly(di-hexyl lactide),poly(ε-caprolactone), and copolymers of these, includingpoly(lactide-co-glycolide), poly(lactide-co-ε-caprolactone),poly(ethylene oxide-co-ε-caprolactone), poly(ethylene oxide-co-lactide),and poly(ethylene oxide-co-lactide-co-glycolide);poly(alkyl)cyanoacrylates, such as poly(isobutyl)cyanoacrylate, andpoly(hexyl)cyanoacrylate.

Thus, in one embodiment, the compositions may contain a plurality ofnanoparticles, at least a portion of which are encapsulated by theresuspending material. Those nanoparticles not encapsulated by theresuspending material are in direct contact with the resuspendingmaterial.

In another embodiment, a portion of the resuspending material isadsorbed to the surface portion of the nanoparticles. The remainingportion of the resuspending material encapsulates the nanoparticles inthe composition. In this embodiment, the resuspending material may actas a surface stabilizer, stabilizing the nanoparticles during theformation process or when present in aqueous suspension, reducing orpreventing aggregation or flocculation of the nanoparticles prior toforming the solid composition of the invention, or when an aqueoussolution is added to the solid nanoparticle composition in order to forman aqueous suspension of the nanoparticles.

In one embodiment, the dextran polymer derivative used as theresuspending material is aqueous soluble.

In another embodiment, the resuspending material is selected from thegroup consisting of dextran succinate, dextran acetate succinate,dextran propionate succinate, dextran acetate propionate succinate, andmixtures thereof and pharmaceutically acceptable salt forms thereof By“pharmaceutically acceptable salt forms thereof” is meant the dextranpolymer derivative is in a pharmaceutically acceptable salt form, orthat the composition was formulated with the dextran polymer derivativein the presence of a counterion when the dry, solid pharmaceuticalcomposition was formed. Exemplary counterions suitable for forming saltforms include sodium, potassium, ammonium, calcium, magnesium, aluminum,iron, and amines. In one embodiment, the dextran polymer derivative isin a sodium salt form, potassium salt form, or ammonium salt form.

In one embodiment, the dextran polymer derivative is in apharmaceutically acceptable salt form. In this embodiment, the saltforms of these materials rapidly dissolve in a neutral pH aqueousenvironment, thereby producing a nanoparticle suspension when the dry,solid composition is administered to an aqueous solution.

The resuspending material constitutes from 5 wt % to 90 wt % of thecombined mass of (1) the resuspending material and (2) thenanoparticles. The resuspending material is present in a sufficientamount so that a solid composition forms a nanoparticle suspension whenadministered to an aqueous use environment. Furthermore, a sufficientamount of resuspending material is present to prevent or retardagglomeration of the nanoparticles into larger particles followingadministration to an aqueous use environment. In one embodiment, theresuspending material constitutes from 10 wt % to 75 wt % of thecombined mass of (1) the resuspending material and (2) thenanoparticles. In another embodiment, the resuspending materialconstitutes from 15 wt % to 50 wt % of the combined mass of (1) theresuspending material and (2) the nanoparticles. In still anotherembodiment, the resuspending material constitutes at least 10 wt % ofthe combined mass of (1) the resuspending material and (2) thenanoparticles. In still another embodiment, the resuspending materialconstitutes at least 20 wt % of the combined mass of (1) theresuspending material and (2) the nanoparticles. In yet anotherembodiment, the resuspending material constitutes at least 25 wt % ofthe combined mass of (1) the resuspending material and (2) thenanoparticles. In another embodiment, the resuspending materialconstitutes at least 40 wt % of the combined mass of (1) theresuspending material and (2) the nanoparticles. In another embodiment,the resuspending material constitutes at least 50 wt % of the combinedmass of (1) the resuspending material and (2) the nanoparticles.

Compositions of Crystalline and Semi-Crystalline Active Agent

In another embodiment, the active agent is present in the dextranpolymer derivative in the crystalline state. In yet another embodiment,the composition comprises particles that consist of single crystals ofactive agent coated with the dextran polymer derivative. In anotherembodiment, the composition comprises particles that consist of aplurality of crystals of active agent distributed in a continuous phasecomprising the dextran polymer derivative. In still another embodiment,the active agent is in a form selected from at least one of crystallineand semi-crystalline active agent having a size of less than 400 nm inat least one dimension. In yet another embodiment, the active agent isdistributed homogenously throughout the continuous phase comprising thedextran polymer derivative and optionally other excipients.

By “semi-crystalline” is meant crystalline active agent having thedextran polymer derivative incorporated into the crystals, crystalscontaining crystal defects, or semi-crystalline structures which takethe form of sheets, tubes, or other structures in which the active agentis ordered but is not in the lowest solubility, bulk crystalline formalone. When the active agent is small crystals, the crystals need onlybe small in at least one dimension, but may be small in two or all threedimensions. The small crystals generally have less than about 200crystal repeat units in at least one dimension. Although crystal repeatunits can vary widely in size, they are generally less than about 2 nmin size and thus small crystals will generally be less than about 400 nmin at least one dimension. In one embodiment, the active agent is in theform of small crystals having a size of less than 200 nm in at least onedimension. In yet another embodiment, the active agent is in the form ofsmall crystals having a size of less than 100 nm in at least onedimension.

In contrast, by “bulk crystalline form alone” is meant crystallineactive agent in which the crystals exhibit long range order, forexample, having at least about 200 repeat units in the shortestdimension, and in which no polymer is present.

In this embodiment, the active agent exhibits physical characteristicsthat are distinct from both active agent in the bulk crystalline formalone and active agent in a non-crystalline or amorphous form. Onemethod for evaluating the physical characteristics of the active agentin the composition is powder x-ray diffraction. In this embodiment, theactive agent in the composition, when characterized using powder x-raydiffraction, exhibits an x-ray diffraction pattern that is differentthan bulk crystalline active agent alone. Active agent that is presentin a form selected from at least one of crystalline and semi-crystallineactive agent having a size of less than 400 nm in at least onedimension, exhibits a diffraction pattern with reflections, scatteringlines, or “peaks” that are broader, less well defined, smaller and/ormissing compared to the reflections, scattering lines, or peaks presentin the diffraction pattern of active agent in the bulk crystalline formalone. Throughout the remainder of this application, the term “peak”refers to the local maximum for a plot of scattered x-ray intensityversus scattering angle. For principal peaks, active agent in a formselected from at least one of crystalline and semi-crystalline activeagent having a size of less than 400 nm in at least one dimension, mayhave a full width at half-height that is at least 1.1 fold that of thecorresponding principal peak width at half-height for the active agentin bulk crystalline form alone. For example, if the full-width athalf-height for the principal peak of crystalline active agent is 0.5°,the full-width at half-height of the corresponding principal peak ofactive agent which is present in a form selected from at least one ofcrystalline and semi-crystalline active agent having a size of less than400 nm in at least one dimension, is at least 0.55°. By “principal peak”is meant a peak in the scattered x-ray intensity versus scattering angleplot that may be differentiated from the baseline and/or other peaks.The full-width at half-height may be even broader, and may be at least1.25 fold, 2 fold or 3 fold or greater that of the correspondingprincipal peak of active agent in bulk crystalline form alone.

Peak widths may be compared for diffractograms from any conventionalPowder X-ray Diffraction (PXRD) instrument. One such method for thecollection of diffractograms would be to use a Bruker AXS D8 Advancediffractometer that is equipped with a Gobel mirror to focus the x-raysinto a parallel beam, a Soller slit to reduce axial divergence of thebeam before it impacts the sample, and a thin film attachment to collectonly the properly diffracted x-rays at any specific collection angle.PXRD instruments functioning in such a manner should be capable ofcollecting data such that a 1.1-fold change in the width of a principalpeak would be readily distinguishable from the random variation observedupon repeated measurement of the same sample.

Likewise, active agent present in a form selected from at least one ofcrystalline and semi-crystalline active agent having a size of less than400 nm in at least one dimension, has a diffraction pattern that differsfrom pure amorphous (i.e., non-crystalline) active agent. Thediffraction pattern for active agent present in a form selected from atleast one of crystalline and semi-crystalline active agent having a sizeof less than 400 nm in at least one dimension, has some peaks,indicating some degree of crystallinity of the active agent. Incontrast, active agent in the amorphous form exhibits no distinct peaks.Amorphous active agent may exhibit one or two extremely broad peaks,often termed “an amorphous halo.” Active agent present in a formselected from at least one of crystalline and semi-crystalline activeagent having a size of less than 400 nm in at least one dimension,exhibit one or more peaks that are narrower and extend above theamorphous halo.

Thermal techniques may also be used to characterize the state of theactive agent. In general, the glass transition temperature (Tg) of acomposition of active agent and polymer is a function of the amount ofactive agent that is in the amorphous form. For a composition comprisingactive agent present in both the amorphous form and in a form selectedfrom at least one of crystalline and semi-crystalline active agenthaving a size of less than 400 nm in at least one dimension, only theactive agent which is amorphous exhibits a Tg. When the glass transitiontemperature of the dextran polymer derivative is greater than that ofthe active agent, the Tg of a composition of active agent and dextranpolymer derivative is greatest and near that of the polymer when all ofthe active agent is present in a form selected from at least one ofcrystalline and semi-crystalline active agent having a size of less than400 nm in at least one dimension. That is, little, if any of the activeagent is molecularly dispersed in the polymer as amorphous active agent.In contrast, the Tg of a composition of dextran polymer derivative andactive agent is lowest when very little or none of the active agent inthe composition is present in a form selected from at least one ofcrystalline and semi-crystalline active agent having a size of less than400 nm in at least one dimension, but rather is dispersed throughout thepolymer in the amorphous state. In such cases the Tg of the materialapproaches the Tg of a homogeneous solid amorphous dispersion consistingessentially of the active agent and polymer. Thus, by measuring the Tgof a composition of active agent and polymer, the percentage of activeagent that is present in a form selected from at least one ofcrystalline and semi-crystalline active agent having a size of less than400 nm in at least one dimension, and the percentage of active agentdispersed in the amorphous state may be determined. Differentialscanning calorimetry (DSC) may be used to measure the glass transitiontemperature of such compositions.

The amount of active agent in the composition that is present in a formselected from at least one of crystalline and semi-crystalline activeagent having a size of less than 400 nm in at least one dimension, mayvary, but is generally greater than about 40 wt % of the active agentpresent in the composition. Any remaining active agent may be present inan amorphous form or crystalline form. In one embodiment, even higherpercentages of active agent may be present in a form selected from atleast one of crystalline and semi-crystalline active agent having a sizeof less than 400 nm in at least one dimension. Thus, in one embodiment,the amount of active agent present in a form selected from at least oneof crystalline and semi-crystalline active agent having a size of lessthan 400 nm in at least one dimension, may be at least 50 wt %, at least60 wt %, at least 75 wt %, or at least 90 wt % of the total amount ofactive agent in the composition.

Compositions comprising active agent and a dextran polymer derivativewherein the active agent is present in a form selected from at least oneof crystalline and semi-crystalline active agent having a size of lessthan 400 nm in at least one dimension, may be prepared according to anytechnique that results in a solid having active agent present in a formselected from at least one of crystalline and semi-crystalline activeagent having a size of less than 400 nm in at least one dimension. Inone method, a solid dispersion of the active agent and dextran polymerderivative is initially formed, as described herein. In one embodiment,at least 90 wt % of the active agent in the solid dispersion isnon-crystalline. The solid dispersion is then treated to increase themobility of the active agent in the dispersion. By “mobility” is meantthe movement or diffusion of the active agent through the dispersion.The initial solid amorphous dispersion may be treated by elevating thetemperature of the dispersion, treating the dispersion with a mobilityenhancing agent, or both. The mobility enhancing agent may be either aliquid or vapor. The mobility enhancing agent should be capable ofplasticizing the dextran polymer derivative, or lowering the glasstransition temperature of the dispersion. However, the mobilityenhancing agent should not cause the active agent to become too solublein the dispersion. The mobility enhancing agent lowers the glasstransition temperature of the dispersion, thus increasing the mobilityof the active agent in the dispersion. Suitable mobility enhancingagents include water, methanol, ethanol, propanol, butanol, carbondioxide, acetone, methylethyl ketone, methyl iso-butyl ketone,acetonitrile, tetrahydrofuran, ethyl acetate, methylene chloride,toluene, and 1,1,1-trichloroethane, as well as mixtures of suchmaterials.

In general, the compositions are prepared under conditions which causethe active agent to convert rapidly from the non-crystalline state to aform selected from at least one of crystalline and semi-crystallineactive agent having a size of less than 400 nm in at least onedimension. Rapid conversion during treatment may cause the active agentto become “trapped” in small active agent-rich regions that areseparated from one another by active agent-poor regions. In contrast,active agent that is allowed to crystallize slowly, especially at lowertemperatures, will tend to form large crystals. Once a substantialportion of the active agent is present in active-agent-rich regionsembedded or interspersed within the active agent-poor, polymer-richregions, the mobility of the active agent is greatly decreased due to(1) the reduced concentration of active agent in the polymer-richregions and (2) a decreased diffusion coefficient for the active agentin the polymer. This decrease in the diffusion coefficient of the activeagent is particularly the case when the glass transition temperature ofthe non-crystalline active agent is less than the glass transitiontemperature of the dextran polymer derivative. This reduced active agentmobility prevents the active agent from aggregating into larger regionsof active agent which may crystallize into larger, lower energycrystalline regions. The result is that the active agent becomes trappedin the polymer as small crystals of the active agent in a form selectedfrom at least one of crystalline and semi-crystalline active agenthaving a size of less than 400 nm in at least one dimension.

Where the composition is formed by treating a solid dispersion, theinitial solid dispersion of the active agent and dextran polymerderivative may be made according to any known process which results inat least a major portion (at least 60%) of the active agent being in anon-crystalline state. Exemplary mechanical processes include millingand extrusion; melt processes include high temperature fusion, solventmodified fusion and melt-congeal processes; and solvent processesinclude non-solvent precipitation, spray coating and spray drying.

Alternatively, other methods may be chosen for forming the compositionsin which the active agent is converted into in a form selected from atleast one of crystalline and semi-crystalline active agent having a sizeof less than 400 nm in at least one dimension, as the composition isformed. For example, such compositions may be formed by wet milling ofthe active agent using an aqueous solution of the dextran polymerderivative.

Delivery Routes and Methods of Treatment

In one embodiment, the invention provides a method of treating ananimal, including humans, in need of therapy comprising administering acomposition comprising an active agent and a dextran polymer derivativeto an animal via a mode selected from the group consisting of oral,buccal, mucosal, sublingual, intravenous, intra-arterial, intramuscular,subcutaneous, intraperitoneal, intraarticular, infusion, intrathecal,intraurethral, topical, subdermal, transdermal, intranasal, inhalation,pulmonary tract, intratracheal, intraocular, ocular, intraaural,vaginal, and rectal.

In one embodiment, the composition comprising an active agent and adextran polymer derivative is intended for oral, buccal, mucosal, orsublingual delivery. In this embodiment, the composition may be in theform of a powder that is incorporated into a suitable oral dosage form,such as tablets, capsules, caplets, multiparticulates, films, rods,suspensions, powders for suspension, and the like. Alternatively, thecomposition may be granulated prior to incorporation into a suitabledosage form.

In another embodiment, the composition comprising an active agent and adextran polymer derivative is intended for intravenous, intra-arterial,intramuscular, subcutaneous, intraperitoneal, intraarticular, infusion,intrathecal, intraocular, or intraurethral delivery. In this embodiment,the composition may be in the form of a suspension or solution, suitablefor injection via a needle, for introduction to an IV bag or bottle, ordelivered via an appropriate catheter to the intended delivery site. Inone embodiment, the composition is formulated as a dry powder or solid,that is then reconstituted into a suspension or solution prior delivery.Formulating the composition as a dry powder or solid typically improvesthe chemical and/or physical stability of the composition. The drypowder or solid is then mixed with a liquid, such as water suitable forinjection or other liquid, to form a suspension or solution that maythen be delivered via the chosen route. In still another embodiment, thecomposition is delivered in the form of a depot that controls orotherwise modifies the rate of release of active agent from the depot.The depot may be formed prior to delivery, or may be formed in situafter delivery. Such depots can be in the form of suspensions or can bein the form of a monolith such as a film or rod. The active agent may bereleased very rapidly by dissolution of the composition when a solubleor enteric or dispersible form of the dextran polymer derivative isused. Alternatively, the active agent may be released over hours, days,or even many months by utilizing a poorly aqueous soluble form of thedextran polymer derivative.

In another embodiment, the composition comprising an active agent and adextran polymer derivative is intended for topical delivery. In thisembodiment, the composition may be formulated into appropriate creams,transdermal patches, and the like, as is well-known in the art.

In another embodiment, the composition comprising an active agent and adextran polymer derivative is intended for inhalation. As used herein,the term “inhalation” refers to delivery to a patient through the mouthand/or nose. In one embodiment, the dry powder suitable for inhalationis delivered to the “upper airways.” The term “upper airways” refers todelivery to nasal, oral, pharyngeal, and/or laryngeal passages,including the nose, mouth, nasopharynx, oropharynx, and/or larynx. Inanother embodiment, the dry powder suitable for inhalation is deliveredto the “lower airways.” The term “lower airways” refers to delivery tothe trachea, bronchi, bronchioles, alveolar ducts, alveolar sacs, and/oralveoli.

In one embodiment, the particles have a mass median aerodynamic diameter(MMAD) of 5 to 100 μm. In another embodiment, the particles have a MMADof 10 to 70 μm. In yet another embodiment, the particles have an averagediameter of 50 μm. In one embodiment, such particles are used in devicesdesigned for delivery of particles to the upper airways. In anotherembodiment, such particles are used in devices designed for delivery ofparticles via the nose.

In one embodiment, the compositions may be formulated as a dry powderfor use in a suitable inhalation device, such as a conventional drypowder inhaler. In another embodiment, the powders may be packaged in apacket suitable for insertion into a dry powder inhaler. Suitable drypowder inhalers typically rely on a burst of inspired air that is drawnthrough the unit to deliver the powder to the desired location. Inanother embodiment, the compositions may be administered as aqueoussolutions or suspensions, or as solutions or suspensions in propellants,using, for example, a metered-dose inhaler. In this embodiment, thesolution or suspension is aerosolized by liquid nebulizers employingeither hydraulic or ultrasonic atomization. Compressor-driven nebulizersmay also be employed, which may use a suitable propellant.

In another embodiment, the composition comprising an active agent and adextran polymer derivative is intended for ocular or intraauraldelivery. In this embodiment, the compositions may be formulated intoappropriate suspensions, creams, fluids, drops or other suitable formsfor administration.

In another embodiment, the composition comprising an active agent and adextran polymer derivative is intended for vaginal or rectal delivery.In this embodiment, the compositions may be formulated into appropriatecreams, pastes, suppositories or other suitable forms foradministration.

For effective delivery, the compositions comprising the active agent anda dextran polymer derivative may be combined with other excipients anddosage form ingredients in essentially any manner that does notsubstantially alter the active agent's activity. The excipients may beeither physically mixed with the compositions or included in thecomposition itself. Such formulation excipients are well known in theart as described in Remington: The Science and Practice of Pharmacy(20^(th) Ed. 2000). Generally, excipients such as matrix materials,fillers, diluents, disintegrating agents, solubilizers, complexingagents, pigments, binders, lubricants, glidants, flavorants, and soforth may be used for customary purposes and in typical amounts withoutadversely affecting the properties of the compositions.

In one embodiment, a dosage form comprises the composition comprisingthe active agent and the dextran polymer derivative, wherein thecomposition comprising the active agent and dextran polymer derivativeconstitute at least 10 wt % of the dosage form. In some instances thedosage form constitutes even greater amounts of the compositioncomprising the active agent and dextran polymer derivative. Thus, thecomposition comprising the active agent and dextran polymer derivativemay constitute at least 20 wt %, at least 30 wt %, at least 40 wt %, oreven at least 50 wt % of the dosage form.

Other features and embodiments of the invention will become apparentfrom the following Examples that are given for illustrating theinvention rather than for limiting its intended scope.

EXAMPLES Dextran Polymer Derivatives

Polymer 1, dextran propionate succinate, having the degree ofsubstitution shown in Table 1, was synthesized using the followingprocedures. First 90 g of dextran having a molecular weight of 10,000daltons (available from Amersham Sciences, Piscataway, N.J.) was addedto 495 g of formamide at 50° C. in a 1 L round bottom flask fitted witha glass jacket heated with mineral oil and an overhead mixer paddlestirring at 150 rpm. After 1 hour 30 g of sodium propionate was added tothe mixture and stirred for 2.5 hours. To this, 195 g of propionicanhydride was added in 30 g increments over 30 minutes while the mixturestirred at 325 rpm. Finally, 13.5 g of succinic anhydride was added.After one hour the stir rate was reduced to 150 rpm and the solution wasstirred overnight.

The polymer was precipitated by pumping 200 mL aliquots of polymersolution into a blender containing 1500 mL water and blended for 45seconds. The solids were collected using a large Buchner funnel andWhatman type 113 filter paper. The solids were then washed in a 5 gallonplastic container containing 12 L water and stirred using an overheadmixer on a low setting for 20 minutes. The washed polymer was againfiltered and collected as described above and blended in aliquots in theblender with water. The polymer/water mixture from the blender wasplaced into a 5 gallon plastic container with 7.5 L water and stirred byoverhead mixing for 20 minutes. The polymer was collected by filtrationas described above. The wash method was repeated twice more using thefiltered polymer and 12 L water, stirring with overhead mixing for 20minutes each time. Finally, the wet polymer was spread onto a tray anddried in a 40° C. oven overnight.

Reverse phase high-performance liquid chromatography (HPLC) was used tocalculate the degree of substitution of propionate and succinate groups.For measurement of free acid content, polymer was dissolved in pH 7.4phosphate buffer at a concentration of 12 mg/mL for 4 hours, thendiluted 1:1 with 0.1% H₃PO₄ to a final pH of approximately 3. Formeasurement of propionate and succinate groups the polymer washydrolyzed in 1N sodium hydroxide for 4 hours at a concentration of 3mg/mL, and then diluted 1:1 to a final pH of approximately 3. HPLCanalysis was performed on a Phenomenex Aqua C18 column with a pH 2.8phosphate buffer eluent at a flow of 1 mL/min, and UV detection at 215nm. Degree of substitution was calculated using the determined amount ofanhydride and free acid of the propionate and succinate groups. Resultsfrom degree of substitution analysis are shown in Table 1.

Dynamic Vapor Sorption (DVS) was used to determine water uptake. Thepolymer was weighed into DVS pans in 10 to 50 mg aliquots. The polymersample was equilibrated to 0% relative humidity (RH) in the DVS andweighed. The polymer sample was then equilibrated to 90% RH and weighed.Water uptake is the difference in mass of the sample at 90% RH and at 0%RH. The measured polymer properties are shown in Table 1. Forcomparison, the properties of underivatized dextran are included inTable 1 as Polymer C-1.

TABLE 1 Molecular Water Weight of Uptake Tg at Starting Pro- Suc- at 90%50% Dextran Acetate pionate cinate RH RH Polymer Type* (daltons) DS DSDS (wt %) (° C.) C-1 Dextran 10,000 0 0 0 26.8  46-50 1 DPS 10,000 0 1.90.23 8.4 ND* 2 DAS 10,000 1.6 0 0.3 8.5 75 3 DPS 3,000 0 1.8 0.6 7.7 344 DPS 5,000 0 1.8 0.4 7.3 72 5 DPS 20,000 0 1.8 0.2 7.8 85 6 DAS 10,0002 0 0.5 ND ND 7 DS 5,000 0 0 0.8 ND ND 8 DS 5,000 0 0 1.3 ND ND 9 DS5,000 0 0 2.5 ND ND 10 DP 5,000 0 0.8 0 ND ND 11 DP 5,000 0 1.8 0 ND ND12 DP 10,000 0 1.3 0 ND ND 13 DPS 10,000 0 1.3 0.2 ND ND 14 DPS 5,000 00.5 0.7 ND ND 15 DAS 10,000 1.6 0 0 8.7 60 16 DPS 5,000 0 0.5 0.4 ND ND17 DPS 10,000 0 2.3 0.8 ND 70 18 DPS 10,000 0 1.3 0.2 ND ND 19 DPS10,000 0 1.3 1.4 ND ND *Types: DP = dextran propionate; DA = dextranacetate; DS = dextran succinate; DPS = dextran propionate succinate; DAS= dextran acetate succinate; DAPS = dextran acetate propionate succinate**ND = not determined.

Polymer 2, dextran acetate succinate, having the degree of substitutionshown in Table 1, was synthesized using the following procedure. First30 g of dextran having a molecular weight of 10,000 Daltons and 10 g ofsodium acetate were added to 100 mL formamide at 50° C. in a glasscontainer and magnetically stirred. To this, 60 g of acetic anhydridewas added and stirred for 15 hours. Next, 8 g of succinic anhydride wasadded and the solution was stirred for 6 hours. After 21 hours thepolymer was precipitated by pouring aliquots of the reaction mixtureinto 750 mL supersaturated brine in a blender. Allowed mixture to settleand recovered polymer to dry over night. After this, 350 mL of acetonewas added to dissolve the polymer and separate out the salts. Themixture was re-precipitated in 750 mL acidified water and then copiousamounts of sodium chloride were added and a yellow gummy substance onthe top of the mixture was removed. All solids were re-dissolved in 250mL acetone. The acetone was then removed by roto-evaporation. Finally,the polymer was collected by filtration and vacuum dried for severalhours. HPLC degree of substitution determination and DVS analysis wereperformed as described for polymer 1.

The Tg of the polymer was determined using modulated differentialscanning calorimetry (mDSC) as follows. Samples of the polymer (about 10mg) were equilibrated at 50% RH overnight in an environmental chamber atambient temperature. The samples were then loaded into pans and sealedinside the environmental chamber. The sample was then analyzed on aQ1000 mDSC (TA Instruments, New Castle, Delaware). Samples were scannedover the temperature range of 0° C. to 200° C., at a scan rate of 2.5°C./min, and a modulation rate of ±1.5° C./min. The Tg was calculatedbased on half height. The Tg is also reported in Table 1.

Polymer 3, dextran propionate succinate, having the degree ofsubstitution shown in Table 1, was synthesized using the followingprocedure. First dextran propionate was synthesized by adding 30 g ofdextran having a molecular weight of 3,000 daltons to 150 mL formamidein a glass container and stirring magnetically until dissolved. To this,10 g of sodium propionate was added and the mixture was heated to 50° C.Next, 50 g of propionic anhydride was added with vigorous stirring. Thestir rate was reduced and the solution stirred overnight. The polymerwas then precipitated by pouring the solution into a glass containercontaining 2500 mL water then saturating with sodium chloride. The solidpolymer was collected and transferred to a small beaker. The aqueousportion was discarded and the residual solids left in the glasscontainer were dissolved with 200 mL acetone and added to the collectedpolymer in the small beaker. This solution was precipitated into 2 Lwater and saturated with sodium chloride. The solids were collected anddissolved as described above. The mixture was combined with 200 mLisopropyl alcohol (IPA) and rotary evaporated to dryness. The remainingsolids were dissolved in 100 mL acetone and vacuum filtered through a 5μm nylon filter to remove salts. The acetone was removed by rotaryevaporation and the remaining solids consisting of dextran propionatewere dried under vacuum.

The dextran propionate described above (8.8 g total) was then dissolvedin 80 mL propionic acid with 8.8 g sodium propionate and 2.6 g succinicanhydride, stirring at 85° C. for 7.5 hours. The heat was turned off andthe mixture sat overnight. The polymer was precipitated by adding thesolution to 800 mL rapidly stirred water in a 1 L beaker and thensaturating the solution with sodium chloride. The precipitated polymerwas collected and dissolved in 50 mL acetone. The rinse step wasrepeated twice more, and then 200 mL IPA was added and the solventremoved with rotary evaporation. The remaining solids were dried undervacuum. The solids were then dissolved into 200 mL acetone and vacuumfiltered through a 0.2 μm nylon filter to remove salts. The remainingsolution was rotary evaporated and the solids dried under vacuum.

HPLC degree of substitution determination and DVS analysis wereperformed as described for polymer 1.

Polymer 4, dextran propionate succinate, having the degree ofsubstitution and water uptake shown in Table 1, was synthesized usingthe following procedure. First dextran propionate was synthesized byadding 468 g formamide to a reaction apparatus as described for Polymer1, stirring at 180 rpm for 30 minutes. To this, 124 g dextran having amolecular weight of 5,000 daltons was added and stirred until dissolved.Next, 44 g sodium propionate was added and stirred until dissolved.Finally, 268 g propionic anhydride was added and the mixture stirredovernight. The solution was pumped from the reactor into a beaker usinga peristaltic pump. Polymer was precipitated out of solution byquenching into water; 100 mL aliquots were added to 1.5 L water in ablender as described for polymer 1. The water layer was poured off and1.5 L water was added to the precipitated polymer. The polymer was thenblended for 1 minute. Next, the polymer was collected in a Buchnerfunnel with a Whatman 113 filter, and then placed in a 5 galloncontainer. After all 9 polymer aliquots were quenched and placed in thecontainer, 10 L of water was added and the mixture was stirred for atleast 15 minutes with an overhead stirrer. The solids were vacuumfiltered as described above to remove the water. The large 10 L washeswere repeated twice more. The solids consisting of dextran propionatewere transferred to a tray lined with foil and dried overnight at 40° C.and 0 to 15% RH.

To form Polymer 4, 595 g propionic acid was then added to a 1 L reactorusing the same apparatus as for dextran propionate synthesis, exceptthat the jacket temperature was at 87° C. and the impellor was Teflon,stirring at 200 rpm. To this, 60 g of the above dextran propionate wasadded and stirred until dissolved. Next, 60 g of sodium propionate wasadded and stirred for 2 hours. Finally 18 g of succinic anhydride wasadded and stirred at 180 rpm for 2 hours. Solids were precipitated,blended, re-blended, washed, filtered and dried as described above.

HPLC degree of substitution determination and DVS analysis wereperformed as described for polymer 1.

Polymer 5, dextran propionate succinate, having the degree ofsubstitution and water uptake shown in Table 1, was synthesized usingthe procedures described in synthesis of Polymer 4 except that dextranhaving a molecular weight of 20,000 daltons was used as the startingmaterial.

HPLC degree of substitution determination and DVS analysis wereperformed as described for polymer 1.

Polymer 6, dextran acetate succinate, having the degree of substitutionshown in Table 1, was synthesized using the following procedure. First30 g of dextran having a molecular weight of 10,000 Daltons and 10 g ofsodium acetate were added to 100 mL formamide at 50° C. in a glasscontainer and magnetically stirred over night. To this, 75 g of aceticanhydride was slowly added and stirred over night. Next, 12 g ofsuccinic anhydride was added and the solution was stirred for 6 hours.After 23 hours the polymer was precipitated by pouring aliquots of thereaction mixture into 750 mL acid/brine in a blender. Allowed mixture tosettle and collected via Buchner funnel and filter. All solids wereblended with 500 mL water. The solids were then collected by filteringthrough a Buchner funnel with filter paper. The solids were thendissolved in 350 mL acetone and stirred for 3 days. Precipitatedaliquots of solution in acidified water and let settle. The solids werecollected by filtering through a Buchner funnel and vacuum desiccated todry.

HPLC degree of substitution determination was performed as described forpolymer 1.

Polymer 7, dextran succinate, having the degree of substitution shown in

Table 1, was synthesized using the following procedures. First 249.5 gof dextran having an average molecular weight of 5,000 Daltons(available from Pharmacosmos, Holbaek, Denmark) was added to 473.1 g offormamide at 50° C. in a 1 L round bottom flask fitted with a glassjacket heated with mineral oil and an overhead mixer paddle stirring at150 rpm. After complete dissolution, typically less than 1 hr, 83.3 g ofsodium propionate was added to the mixture and stirred for approximately2 hours. To this, 79.5 g of succinic anhydride (Fluka Chemical) wasadded. After approximately 30 minutes a 51.3 g sample was removed usinga peristaltic pump. To the remaining solution in the reactor, anadditional 88.2 g of succinic anhydride was added. After 1 hr a 50 gsample was collected and washed as follows. Polymer 7 was precipitatedusing a 20:1 methanol to polymer ratio, two times, decanting the liquidbetween washes. The solid material was dried in a 40° C. oven overnight.The material was hardened and was milled with a mortar and pestle inmethanol, and then washed with acetone, filtered, and re-dried.

Polymer 8, dextran succinate, having the degree of substitution shown inTable 1, was synthesized using the following procedures. To the solutionremaining in the reactor after collection and isolation of Polymer 7 wasadded 68.7 g of succinic anhydride and allowed to react forapproximately 1 hr. A 50.08 g sample was removed using a peristalticpump and an additional 64.7 g succinic anhydride was added incombination with 51.4 g of propionic acid to increase solubility of thesubstrate. This reaction was allowed to proceed overnight and 50.1 g ofpolymer 8 was removed from the reactor. Polymer 8 (35 mL) was mixed with700 mL of acetone at 250 rpm and up to 1400 rpm in a Silverson highshear mixer. The resultant particles were fine and did not settlequickly. The material was filtered and dried overnight at 40° C. Thedried material was mixed to break up a thin film on the top of a finepowder, and re-dried.

Polymer 9, dextran succinate, having the degree of substitution shown inTable 1, was synthesized using the following procedures. To the solutionremaining in the reactor after collection and isolation of Polymer 8 wasadded a 61.9 g aliquot of succinic anhydride and allowed to react tocompletion as judged by FTIR. The contents of the reactor (polymer 9)were removed by pumping into a glass vessel.

Polymer 9 was washed at a 20:1 (g/g) acetone:polymer ratio in aSilverson high shear mixer at 2200 rpm and up to 5000 rpm. Smallparticles were obtained. Subsequent washes were performed using acetone.The polymer was filtered and dried overnight in a 40° C. oven. The driedmaterial was remixed to break up a thin film on the top of a finepowder, and re-dried.

Polymer 10, dextran propionate, having the degree of substitution shownin Table 1, was synthesized using the following procedures. First 210 gof dextran having an average molecular weight of 5,000 Daltons(available from Pharmacosmos, Holbaek, Denmark) was added to 397.4 g offormamide (Sigma-Aldrich) at 50° C. in a 1 L round bottom flask fittedwith a glass jacket heated with mineral oil and an overhead mixer paddlestirring at 300 rpm. After complete dissolution, 74.72 g of sodiumpropionate (Sigma Aldrich) was added to the mixture and stirred forapproximately 1 hour. A background spectrum was collected using FTIR. Tothis, 196.3 g of propionic anhydride (Sigma Aldrich) was added while themixture stirred at 325 rpm. After approximately 1 hour, when thereaction neared completion as judged by FTIR, a 50 g sample was removedfrom the reactor using a peristaltic pump.

The polymer was precipitated by washing twice with 400-500 mL each ofacetone. For each wash, the polymer and acetone were thoroughly mixedusing vortex and manual shaking The solids were collected each timeusing a large Buchner funnel and Whatman type 113 filter paper. Finally,the wet polymer was spread onto a tray and dried in a 40° C. ovenovernight. Any pellets found were crushed and dried further.

Polymer 11, dextran propionate, having the degree of substitution shownin Table 1, was synthesized using the following procedures. To thesolution remaining in the reactor after collection and isolation ofPolymer 10 was added a 79.4 g aliquot of propionic anhydride and themixture was allowed to react to apparent completion as judged by FTIR(approximately 40 minutes). A 50 g sample was removed from the reactor.Propionic anhydride was added (61.7 g) and allowed to react to apparentcompletion. A 50 gram sample was removed by peristaltic pump, andisolated by washing twice with approximately 500 mL of water each timein a WaringPro 3 HP blender, and decanting of the liquid solution. Theflocculated material was washed further in a 5 gallon bucket withapproximately 5 L of water using an overhead stirrer. The polymer wascollected by filtration using a large Buchner funnel and Whatman type113 filter paper. The wet polymer was spread onto a tray and dried in a40° C. oven overnight.

Polymer 12, dextran propionate, having the degree of substitution shownin Table 1, was synthesized using the following procedure. First 165 gof dextran having a molecular weight of 10,000 Daltons and 55 g ofsodium propionate were added to 495 g formamide at 50° C. in a 1 L glassreactor equipped with a Heidolph mixer and pitched blade turbine. Tothis solution, 192.7 g of propionic anhydride was added and stirred at150 rpm for 1.5 hours. The reaction went to completion as measured byFTIR. Next about 299 g of the reaction mixture was removed from thereactor and quenched in two aliquots by adding about 150 g of reactionmixture to 1.5 L water saturated with NaC1 (e.g., brine). The mixturewas blended in a blender, vacuum filtered using Watman filter paper torecover the polymer, and resuspended and washed with 1.7 L salt brinefor 6 total washes. Upon completion of washing, the polymer was airdried, and then dissolved in about 500 μm of methanol. The salt crystalswere filtered out of the methanol/polymer solution by vacuum filtrationusing a Watman glass microfibre filter. The final solution was clearmethanol/polymer. This solution was spray dried in a Niro PSD-1 spraydryer and residual methanol was removed in a tray dryer for 24 hours at40° C. and <10% RH. The final polymer was collected and analyzed forsubstitution as previously described.

Polymer 13, dextran propionate succinate, having the degree ofsubstitution shown in Table 1, was synthesized using the followingprocedure. First 30 g of dextran having a molecular weight of 10,000Daltons and 10 g of sodium propionate were added to 150 mL formamide at50° C. in a glass container and magnetically stirred until dissolved. Tothis, 50 g of propionic anhydride was added and stirred for 30 minutesat 50° C. Next, 9 g of succinic anhydride was added and the solution wasstirred overnight at 50° C. After 17.5 hours the polymer wasprecipitated by pouring aliquots of the reaction mixture into 750 mL pH4 brine. This was followed by two washes of solids in 750 mL deionizedwater in a blender. The final wash in DI water was followed by completedissolution of solids in 200 mL acetone. The solution was filteredthrough a 5 μm nylon filter. 50 mL of IPA was added and the IPA was thenremoved by roto-evaporation. Finally, the polymer was collected byfiltration and dried under vacuum. The solids were then dissolved in 400mL acetone and sent for spray drying.

HPLC degree of substitution determination was performed as described forpolymer 1.

Polymer 14, dextran propionate succinate, having the degree ofsubstitution shown in Table 1, was synthesized using the followingprocedures. First 140.0 g of dextran having an average molecular weightof 5,000 Daltons (available from Pharmacosmos, Holbaek, Denmark) wasadded to 265.1 g of formamide at 50° C. in a 1 L round bottom flaskfitted with a glass jacket heated with mineral oil and an overhead mixerpaddle stirring at 150 rpm. After complete dissolution 49.9 g of sodiumpropionate was added to the mixture and stirred for approximately 2hours. To this, 106.7 g of propionic anhydride was added while themixture stirred at 325 rpm. Finally, after approximately 30 minutes,82.7 g of succinic anhydride was added. After one hour the stir rate wasreduced to 150 rpm and the solution was stirred overnight.

The polymer (approximately 450 mL) was pumped into a glass vessel andwashed at a 7:1 (v/v) ratio of acetone to polymer, four times. A stirbar was used for mixing, as well as manual shaking The liquid wasdecanted in between washes. The solids were collected using a largeBuchner funnel and Whatman type 113 filter paper. The polymer was spreadonto a tray and dried in a 40° C. oven overnight.

Polymer 15, dextran acetate, having the degree of substitution shown inTable 1, was synthesized using the following procedure. First 30 g ofdextran having a molecular weight of 10,000 Daltons and 11 g of sodiumacetate were added to 100 mL formamide at 50° C. in a glass containerand magnetically stirred until dissolved. To this, 60 g of aceticanhydride was added and stirred overnight at 50° C. Approximately 24hours later, the reaction was precipitated into 2500 mL acidified (pH 4with acetic acid) brine. The solution was filtered and a sticky polymerwas collected. This was then re-dissolved in methanol. A small amount ofIPA was added to the methanol solution and filtered. Small aliquots wereadded to ethyl acetate in two-1 L round bottom flasks. The remainingsolvent was roto-evaporated off The polymer was then dissolved inacetone, filtered and roto-evaporated again prior to recovery.

Degree of substitution determination was performed using NMR. DVS wasperformed as described for polymer 1.

Polymer 16, dextran propionate succinate, having the degree ofsubstitution shown in Table 1, was synthesized using the followingprocedures. First 150.9 g of dextran having an average molecular weightof 5,000 daltons (available from Pharmacosmos, Holbaek, Denmark) wasadded to 286.1 g of formamide at 50° C. in a 1 L round bottom flaskfitted with a glass jacket heated with mineral oil and an overhead mixerpaddle stirring at 150 rpm. After complete dissolution 52.8 g of sodiumpropionate was added to the mixture and stirred for approximately 2hours. To this, 110.8 g of propionic anhydride was added while themixture stirred at 325 rpm. Finally, after approximately 30 minutes,44.1 g of succinic anhydride was added. After 30 minutes the reactionappeared to be complete as judged by FTIR.

The polymer (approximately 460 mL) was pumped into a glass vessel andwashed at a 7:1 (v/v) ratio of acetone to polymer, four times. A stirbar was used for mixing, as well as manual shaking The liquid wasdecanted in between washes. The solids were collected using a largeBuchner funnel and Whatman type 113 filter paper. The polymer was spreadonto a tray and dried in a 40° C. oven overnight.

Polymer 17, dextran propionate succinate, having the degree ofsubstitution shown in Table 1, was synthesized using the followingprocedures. First 822 g of dextran having a molecular weight of 10,000daltons (available from Pharmacosmos) was added to 3104 g of formamideat 50° C. in a round bottom flask fitted with a glass jacket heated withmineral oil and an overhead mixer paddle stirring at 180 rpm. Afterapproximately 1 hour, 293 g of sodium propionate was added to themixture and stirred. To this, 1681 g of propionic anhydride was addedand stirred.

Polymer 17 was precipitated by pumping 100 mL aliquots of polymersolution into a blender containing 750 mL water and blended. The solidswere decanted and blended again in 750 mL water. The solids werecollected using a large Buchner funnel with a paper filter. The solidswere then washed in a 5 gallon vessel containing approximately 10 Lwater and stirred using an overhead mixer for 15 minutes. The washedpolymer was again filtered and collected as described above and blendedin aliquots in the blender with water. The polymer/water from theblender was placed into a 5 gallon vessel with 10 L water and stirred byoverhead mixing for 15 minutes. This was collected by filtration asdescribed above. The wash method was repeated twice more using thefiltered polymer and 10 L water, stirring with overhead mixing for 15minutes each time. Finally, the wet polymer was spread onto a tray anddried in a 40° C. (20% R.H.) oven overnight.

The dextran propionate described above (30 g) was then dissolved in 600mL propionic acid with 30 g sodium propionate and 36 g succinicanhydride with stirring at 85° C., for 3 hours. Polymer was precipitatedby adding a 200 mL aliquot of polymer solution into a blender containing1.5 L water and blended. The first 1.5 L water was decanted and thepolymer was blended again in 1.5 L water. The solids were collectedusing a large Buchner funnel with a paper filter. The solids were thenwashed in a 5 gallon vessel containing approximately 10 L water andstirred using an overhead mixer for 15 minutes. The washed polymer wasagain filtered and collected as described above and blended in aliquotsin the blender with water. The chopped polymer/water from the blenderwas placed into a 5 gallon vessel with 10 L water and stirred byoverhead mixing for 15 minutes. This was collected by filtration asdescribed above. The wash method was repeated twice more using thefiltered polymer and 10 L water, stirring with overhead mixing for 15minutes each time. Finally, the wet polymer was spread onto a tray anddried in a 40° C. (20% R. H.) oven overnight.

The properties of Polymer 17 were measured using the procedurespreviously described, and are reported in Table 1.

Polymer 18, dextran propionate succinate, having the degree ofsubstitution shown in Table 1, was synthesized using the followingprocedures. To the reaction mixture of Polymer 12 remaining afterremoval of 299 g to isolate Polymer 12, was added 13.36 g succinicanhydride. The solution was stirred at 150 rpm for 3 hours. Next, 340.6g of the reaction mixture was removed from the reactor and quenchedusing water saturated with NaC1, as described above for Polymer 12. Thepolymer isolation and purification procedures were the same as describedfor Polymer 12, except that 1000 g methanol was used to dissolve Polymer18.

Polymer 19, dextran propionate succinate, having the degree ofsubstitution shown in Table 1, was synthesized using the followingprocedures. To the reaction mixture of Polymer 18 remaining afterremoval of 340.6 g to isolate Polymer 18, was added 32.2 g succinicanhydride. The solution was stirred at 150 rpm for 16 hours. Next, thereaction mixture was removed from the reactor and quenched using watersaturated with NaCl. The polymer was washed six times with 1.7 L ofwater saturated with NaCl and vacuum filtered each time as described forPolymer 12. After the brine washes, Polymer 19 was washed once usingwater alone to remove the salt. Finally, the wet polymer was spread ontoa tray and dried in a 40° C. oven overnight.

Active Agents Used in Examples

Active Agent 1 was S-(fluoromethyl)6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate,17-propionate, also known as fluticasone propionate, having thestructure:

Active Agent 1 has a solubility of 0.4 μg/mL in pH 7.4 buffer, and a CLog P value of 3.7. The T_(g) of amorphous Active Agent 1 was determinedby DSC to be 84° C.

Active Agent 2 was propan-2-yl2-{4-[(4-chlorophenyl)carbonyl]phenoxy}-2-methylpropanoate, also knownas fenofibrate, having the structure

Active Agent 2 has a water solubility of about 0.8 μg/mL, a C Log Pvalue of 5.2, and the Tm is 80.5° C.

Active Agent 3 was 3,5-dimethyl2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate,also known as nifedipine, having the structure:

Active Agent 3 has a water solubility of 10 μg/mL, a C Log P value of3.1, and the Tm is 173° C.

Active Agent 4 was 6-(trifluoromethoxy)benzothiazol-2-amine, also knownas riluzole, having the structure

Active Agent 4 has a C Log P value of 3.2, and the Tm is 119° C. ActiveAgent 4 is sparingly soluble in 0.1 N HCl, and very slightly soluble inwater and in 0.1 N NaOH.

Dispersions for Oral Delivery Example 1 Active Agent 1:Polymer 1

A dry powder consisting of particles of a solid dispersion of ActiveAgent 1 was prepared by forming a spray solution containing 0.02 wt %Active Agent 1, 0.18 wt % Polymer 1, 94.81 wt % acetone, 4.99 wt % wateras follows: the active agent and solvents were combined in a 30 Lstainless steel tank and mixed to form a clear solution, then thepolymer was added to the solution and mixed for 30 minutes.

The spray solution was pumped using a Bran & Luebbe (Norderstedt,Germany) metering pump from the 30-L tank to three Schlick(Düsen-Schlick GmbH of Untersiemau, Germany)) 1.5 pressure nozzles.Combined liquid feed was 100 g/minute, (33 g/min/nozzle) at 660 psig,into a Niro (Columbia, Md.) mobile minor Portable Spray-Drier(“PSD-1.”). The PSD-1 was equipped with 9-inch and 4-inch chamberextensions to increase the vertical length of the dryer and theresidence time of the particles in the drying chamber. The inlet dryingnitrogen was flowing at 1370 g/min and heated to 135° C. and introducedto the spray drier equipped with a DHP gas disperser. The exittemperature of the drying gas and evaporated solvents was 55° C. Thedried material was pneumatically conveyed through 2″ ductwork to a6-inch outside diameter cyclone. The resulting solid dispersionparticles were collected in a container attached to the bottom of thecyclone via a butterfly valve.

The so-formed solid dispersion particles consisted of 10 wt % ActiveAgent 1 in Polymer 1. The particles were dried under a vacuum of lessthan about 0.2 atm for 12 hours at 22° C.

The dispersion was analyzed by powder X-ray diffraction (PXRD) using anAXS D8 Advance PXRD measuring device (Bruker, Inc. of Madison, Wis.)following the following procedure. Samples (approximately 100 mg) werepacked in Lucite sample cups fitted with Si(511) plates as the bottom ofthe cup to give no background signal. Samples were spun in the φ planeat a rate of 30 rpm to minimize crystal orientation effects. The x-raysource (KCu_(α), λ=1.54 Å) was operated at a voltage of 45 kV and acurrent of 40 mA. Data for each sample were collected over a period of27 minutes in continuous detector scan mode at a scan speed of 1.8seconds/step and a step size of 0.04°/step. Diffractograms werecollected over the 20 range of 4° to 40°. FIG. 1 shows the diffractionpattern of the dispersion of Example 1, revealing an amorphous halo,indicating the active agent in the dispersion was amorphous.

The Tg of the dispersion was determined using modulated differentialscanning calorimetry (mDSC) as previously described. Samples of thedispersion (about 10 mg) were equilibrated at <5% RH overnight in anenvironmental chamber at ambient temperature. The dispersion had asingle Tg of about 128° C., indicating the active agent in thedispersion was molecularly dispersed in the dextran polymer derivative.

In Vitro Dissolution Performance

The dispersion of Example 1 was tested using a syringe dissolution test.A sufficient amount of the composition of Example 1 was added to asyringe at a concentration of 50 μg/mL if all the active agent haddissolved. The syringe contained 20 mL of a buffer solution at pH 7.4,made by dissolving the following into 1 L of deionized water: 0.368 gcalcium chloride (dihydrate), 0.203 g magnesium chloride (hexahydrate),0.298 g potassium chloride (anhydrous), 6.0193 g sodium chloride, 2.604g sodium bicarbonate (anhydrous), 0.097 g sodium citrate, 0.953 g sodiumacetate, 0.142 g sodium phosphate (dibasic), and 0.0710 g sodiumsulphate (anhydrous). This solution was adjusted to pH 7.42 by addingsufficient 0.1 N HCl. Next 0.1004 g of hydroxypropyl methyl cellulose(E3 grade) and 0.0197 g of L-alpha phosphatidyl choline, which had beendissolved in methanol and then the methanol removed by rotoevaporation,was added and the mixture stirred, then filtered through a 5 μm filter.

After adding the dispersion and the buffer to the syringe, the syringewas periodically inverted to mix the components in the syringe. Thesyringe was fitted with a 0.45 μm Supor PES syringe filter(manufacturer, city, state). After 5 minutes, 1 mL of fluid was pushedthrough the filter into a 2-mL centrifuge tube. A 0.5-mL aliquot ofmethanol was then added to the centrifuge tube, which was then invertedto mix the contents in the tube, followed by centrifugation at 13,000rpm for 1 minute. The supernatant was transferred to another centrifugetube. This procedure was repeated for all timepoints. Samples werefrozen in liquid nitrogen and place on a lyophilizer for 3 days toremove all liquids. To the dried samples was added 100 μL 80/20 (w/w)methanol/water, then 250 μL methanol and the mixture shaken. Sampleswere then centrifuged at 13,000 rpm for 1 minute. Samples were thenanalyzed by high-performance liquid chromatography to determine theconcentration of Active Agent 1 in the samples. The results arepresented in Table 2.

TABLE 2 Sample Time (min) Concentration (μg/mL) Example 1 0 0 5 12.6 1517.0 30 13.5 90 3.7 180 0.3 Control 1 0 0 5 0.25 15 0.30 30 0.10 90 0.24180 0.37

As a control (Control 1), the same test was performed using the sameamount of crystalline Active Agent 1 alone, with no dextran polymerderivative. The results are also shown in Table 2.

The results of these tests are summarized in Table 3. These results showthat the dispersion of Example 1 provided more than 40-fold improvementin C. compared to Control 1.

TABLE 3 Example C_(max) (μg/mL) 1 17.0 Control 1 0.37

Dispersions for Pulmonary Delivery Example 2 Active 1:Polymer 1

A dry powder consisting of particles of a solid dispersion of ActiveAgent 1 was prepared by forming a spray solution containing 0.02 wt %Active Agent 1, 0.18 wt % Polymer 1, 4.99 wt % water, and 94.81 wt %acetone as follows: the active agent and solvent were combined in acontainer and mixed to form a clear solution, then the polymer was addedto the solution and mixed for 3 hours.

The spray solution was pumped from a 10-L stainless steel tank using ametering pump into a spray drier (a Niro type XP Portable Spray-Drierwith a Liquid-Feed Process Vessel (“PSD-1”)), equipped with 3 pressurenozzles (Schlick 1.5 60° ; Dusen Schlick, GmbH of Untersiemau, Germany).The PSD-1 vessel was equipped with 9-inch and 4-inch chamber extensionsto increase the vertical length of the dryer and residence time of theparticles in the drying chamber. The inlet nitrogen gas at a flow of1375g/min was heated to 140° C. and introduced to the spray drier. Theexit temperature of the drying gas was 55° C. The dried material waspneumatically conveyed through 2″ ductwork to a cyclone. The resultingsolid dispersion particles were collected in a 120 mL jar attached tothe bottom of the cyclone via a 2″ butterfly valve.

The so-formed solid dispersion particles were then dried under vacuumdesiccation for 12 hours at room temperature.

In Vitro Inhalation Performance

The dry powder was tested using the NEXT GENERATION PHARMACEUTICALIMPACTOR (NGI), Model 170 (available from MSP Corporation, Shoreview,Minn.). A 15 mg sample of the solid dispersion particles was evaluatedusing the NGI. The results of the NGI evaluation for Example 2 are shownin Table 4.

Differential Scanning Calorimetry (DSC)

DSC was used to measure the glass transition temperature. The soliddispersion samples were equilibrated for a minimum of 14 hours atambient temperature and <5% RH. Sample pans were crimped and sealed inan environmental chamber, then loaded into a Thermal Analysis Q1000Differential Scanning Calorimeter equipped with an autosampler(available from TA Instruments, New Castle, Del.). The samples wereheated by modulating the temperature at ±1.5° C./min, and ramping thetemperature up to 200° C. at 2.5° C./min. The sample had a single Tg at128° C. and no other thermal events, suggesting the composition wasamorphous. This was confirmed by powder X-ray diffraction (PXRD) whichshowed an amorphous halo.

TABLE 4 NGI data Glass-Transition FPF* MMAD** Temperature (° C.) Example(%) (μm) (determined at 50% RH) 2 72 2.9 128 3 75 2.6 Not Determined*FPF—fine particle fraction (less than 4.6 μm) **MMAD—mass medianaerodynamic diameter

Example 3 Active Agent 1:Polymer 9

A dry powder consisting of particles of a solid dispersion of ActiveAgent 1 was prepared by forming a spray solution containing 0.1 wt %Active Agent 1, 0.9 wt % Polymer 7, and 99 wt % acetone as follows: theactive agent and solvent were combined in a container and mixed to forma clear solution, then the polymer was added to the solution and mixedfor 3 hours.

The spray solution was pumped from a 6 L container using a peristalticpump into a spray drier (a Niro type XP Portable Spray-Drier, PSD-1),equipped with a 2-fluid nozzle (spray systems: liquid is 2050 and air is120). The PSD-1 vessel was equipped with 9-inch and 4-inch chamberextensions to increase the vertical length of the dryer and residencetime of the particles in the drying chamber. The inlet nitrogen gas at aflow of 920 g/min was heated to 110° C. and introduced to the spraydrier. The exit temperature of the drying gas was 45° C. The driedmaterial was pneumatically conveyed through 2″ ductwork to a cyclone.The resulting solid dispersion particles were collected in a 500 mL jarattached to the bottom of the cyclone via a 2″ butterfly valve.

The so-formed solid dispersion particles were then dried under vacuumdesiccation for 12 hours at room temperature.

The dry powder was tested using the NEXT GENERATION PHARMACEUTICALIMPACTOR (NGI), Model 170 (available from MSP Corporation, Shoreview,Minn.), using the procedures described in Example 2. The results aresummarized in Table 4.

Example 4 In Vivo of Example 3 Formulation

The dry powder of Example 3 was used in an in vivo test to determine theconcentration of Active Agent 1 in the lung, bronchoalveolar lavagefluid (BALF) and plasma of male Sprague Dawley rats after a singleinhalation exposure to one of three dose levels of an aerosolized drypowder. Aerosols of the dry powder of Example 3 were generated with aPalas Rotating Brush Generator (RGB) 1000 solid particle disperser(Palas GmbH; Karlsruhean, Germany). The dry powder of Example 3 wasloaded into a 14-mm piston and gently packed prior to integration on tothe RBG 1000. The RGB 1000 was operated with a brush rotation speed of1200 revolution/min and a brush feed speed of between 15 and 30 mm/h.Compressed air was added to a final volumetric flow rate ofapproximately 19.5 L/min. Aerosols were directed through approximately24 in of a 1.58-cm (diameter) delivery line. Aerosols transited into aflow-past 36-port nose-only rodent exposure chamber. The chamber exhaustflow rate was adjusted to a volumetric flow rate of approximately 22L/min, slightly higher than the flow rate supplied by the rotating brushaerosol generator.

Prior to dosing, aerosols were collected (from the exposure plenum) on47-mm Zefluor filters (PALL Life Sciences; Ann Arbor, Mich.) at anominal volumetric flow rate of 0.5 L/min. Particle size distributionwas measured using an aerodynamic particle sizer (APS; TSI Model 3321;Shoreview, Minn.). The MMAD for the dry powder of Example 3 using thisaerosol generation technique was determined to be 2.3 μm with ageometric standard deviation (GSD) of 1.6. The concentration of ActiveAgent 1 in the aerosols was determined to range from 0.4 to 0.8 mg/L.

Eighty-one (81) male Sprague Dawley rats were exposed to the dry powderof Example 3 at target concentrations of 0.1, 1.0, and 2.0 mg/L for 30minutes, to achieve target doses of 2, 20, and 40 mg/kg, respectively.Animals were sacrificed at nine specified time points post exposure andblood (plasma), BALF, and lungs were harvested. Samples were stored atapproximately −70° C. before and after analysis. Concentrations ofActive Agent 1 were determined using an LC/MS/MS method, followingliquid-liquid extraction. Tables 5 and 6 summarize the results.

TABLE 5 Dose (mg/kg) Time (hr) 2 20 40 Drug Concentration in Plasma(ng/mL) 0.083 3.85 ± 0.77 31.9 ± 3.0  90.9 ± 8.4  0.25 2.24 ± 0.41 23.9± 1.8  80.1 ± 15.8 0.5 1.93 ± 0.24 16.2 ± 1.8  49.7 ± 20.2 1 1.59 ± 0.4310.5 ± 1.1  29.8 ± 1.5  2 1.17 ± 0.76 9.8 ± 2.1 18.2 ± 4.6  4 0.41 ±0.08 4.1 ± 2.3 7.9 ± 1.9 8 0.13 ± 0.01 1.2 ± 0.5 2.8 ± 1.2 12 0 ± 0 0.54± 0.15 1.5 ± 1.1 24 0.12 ± 0.13 0.18 ± 0.18 0.28 ± 0.14 DrugConcentration in BALF (ng/mL) 0.083 2.8 ± 1.9 23.9 ± 17.1 102 ± 30  0.250 ± 0 10.7 ± 1.5  110 ± 32  0.5 0 ± 0 5.3 ± 2.1 22.8 ± 22  1 0 ± 0 4.4 ±1.7 10.4 ± 7.8  2 0 ± 0 1.9 ± 0.2 2.5 ± 1.3 4 0 ± 0 0 ± 0 0 ± 0 8 0 ± 00 ± 0 0 ± 0 12 0 ± 0 0 ± 0 0 ± 0 24 0 ± 0 0 ± 0 0 ± 0 Drug Concentrationin the Lungs (ng/mL) 0.083 37.5 ± 12.8 387 ± 333 773 ± 144 0.25 20.1 ±8.7  104 ± 66  511 ± 296 0.5 15.6 ± 5.7  45.7 ± 8.8  200 ± 110 1 16.1 ±10.1 48.7 ± 20.8 186 ± 68  2 8.1 ± 1.4 27.6 ± 4.3  73.9 ± 36.8 4 3.4 ±1.0 28.1 ± 14   22 ± 3.9 8 0.74 ± 0.64 7.5 ± 4.4 10.3 ± 3.2  12 0 ± 02.01 ± 0.8  4.6 ± 1.1 24 0.74 ± 1.3  0.35 ± 0.61 0.99 ± 0.89

TABLE 6 Max Dose C_(max) T_(max) AUC_(0-12 hr) Formulation (mg/kg)(ng/mL) (hr) (ng*hr/mL) Example 3 0.1 3.9 0.58 6 1 32 0.58 58 2 96 0.58139 AUC_(0-12 hr) = area under the concentration versus time curve from0 to 12 hours.

NANOPARTICLE EXAMPLES Example 5 Active Agent 2:Polymer 17

For Example 5, nanoparticles containing Active Agent 2 were prepared asfollows. First, 1.0 mg Active Agent 2 and 9.0 mg Polymer 17 weredissolved in 5 mL ethyl acetate to form an organic solution. Next, 2.5mg sodium glycocholate (NaGly) was dissolved in 5 mL deionized water toform an aqueous solution. The organic solution was then poured into theaqueous solution and emulsified for 3 min using a Kinematica Polytron3100 rotor/stator (Kinematica AG, Lucerne, Switzerland) at 10,000 rpm(high-shear mixing). The solution was further emulsified using aMicrofluidizer (Microfluidics [Newton, Mass.] model M-110S F12Y with icebath and cooling coil), for about 6 minutes at 12,500 psi (high-pressurehomogenization). The ethyl acetate was removed from the emulsion using arotary evaporator, resulting in an aqueous suspension of nanoparticles,with a composition ratio of 1:9:2.5 Active Agent 2:Polymer 17:NaGly.

A filter potency test was used to measure the stability of thenanoparticle suspension. Changes in potencies due to particleagglomeration were measured over time using HPLC. The initial potency ofthe unfiltered aqueous nanoparticle suspension was first measured usingHPLC. The suspension was allowed to stand at room temperatureundisturbed to determine suspension stability. After 4 hours and after24 hours, the suspension was filtered using a 1 μm filter and a 50 μLsample was added to 1 mL methanol and analyzed by HPLC. HPLC analysis ofActive Agent 2 was performed using a Zorbax RX-C₁₈ column. The mobilephase consisted of 20/80 10 mM ammonium acetate/acetonitrile. UVabsorbance was measured at 260 nm.

Percent potency remaining was calculated by dividing the filteredconcentration at each time by the initial unfiltered concentration.Suspensions were also examined using optical microscopy. The results areshown in Table 7. The results in Table 7 show that 91% of the potency ofthe nanoparticle suspension of Example 5 is maintained followingfiltration by a 1 μm filter after 24 hours. These results demonstratethat the nanoparticle suspension of Example 5 was stable during storagewith no measurable particle agglomeration.

TABLE 7 DLS of Unfiltered HPLC Potency Suspension (1 μm filtered)Example 5 (nm) (%) Microscopy Initial 159 99 No crystals  4 hours 146 92No crystals 24 hours 156 91 No crystals

Example 6 Active Agent 3:Polymer 1

For Example 6, nanoparticles containing Active Agent 3 were prepared asfollows. First, 1.0 mg Active Agent 3 and 9.0 mg Polymer 17 weredissolved in 5 mL ethyl acetate to form an organic solution. Next, 2.5mg sodium glycocholate (NaGly) was dissolved in 5 mL deionized water toform an aqueous solution. The organic solution was then poured into theaqueous solution and emulsified for 3 min using a Kinematica Polytron3100 rotor/stator (Kinematica AG, Lucerne, Switzerland) at 10,000 rpm(high-shear mixing). The solution was further emulsified using aMicrofluidizer (Microfluidics [Newton, Mass.] model M-110S F12Y with icebath and cooling coil), for about 6 minutes at 12,500 psi (high-pressurehomogenization). The ethyl acetate was removed from the emulsion using arotary evaporator, resulting in an aqueous suspension of nanoparticles,with a composition ratio of 1:9:2.5 Active Agent 3:Polymer 17:NaGly. DLSanalysis resulted in an average diameter of 191 nm with a polydispersityof 0.14.

A filter potency test was used to measure the stability of thenanoparticle suspension. Changes in potencies due to particleagglomeration were measured over time using HPLC. The initial potency ofthe unfiltered aqueous nanoparticle suspension was first measured usingHPLC. The suspension was allowed to stand at room temperatureundisturbed to determine suspension stability. After 4 hours and after22 hours, the suspension was filtered using a 1 um filter and a 50 μLsample was added to 1 mL methanol and analyzed by HPLC.

Percent potency remaining was calculated by dividing the filteredconcentration at each time by the initial unfiltered concentration.Suspensions were also examined using optical microscopy. The results areshown in Table 8. The results in Table 8 show that 91% of the potency ofthe nanoparticle suspension of Example 6 is maintained followingfiltration by a 1 μm filter after 22 hours. These results demonstratethat the nanoparticle suspension of Example 6 was stable during storagewith no measurable particle agglomeration.

TABLE 8 DLS of Unfiltered HPLC Potency Suspension (1 μm filtered)Example 6 (nm) (%) Microscopy Initial 191 100 No crystals  4 hours 16595 No crystals 24 hours 156 95 No crystals

RESUSPENSION EXAMPLES Examples 7-9

Examples 7-9 demonstrate resuspension of nanoparticles using dextranpolymer derivatives. For these examples, nanoparticles containing ActiveAgent 4 were prepared as follows. First, 100 mg Active Agent 4 and 300mg ethylcellulose (ETHOCEL™) were dissolved in 6 mL ethyl acetate toform an organic solution. Next, 20 mg sodium taurocholate (NaTC) wasdissolved in 20 mL deionized water to form an aqueous solution. Theorganic solution was then poured into the aqueous solution andemulsified for 3 min using a Kinematica Polytron 3100 rotor/stator(Kinematica AG, Lucerne, Switzerland) at 10,000 rpm (high-shear mixing).The solution was further emulsified using a Microfluidizer(Microfluidics [Newton, Mass.] model M-110S F12Y with ice bath andcooling coil), for about 6 minutes at 12,500 psi (high-pressurehomogenization). The ethyl acetate was removed from the emulsion using arotary evaporator, resulting in an aqueous suspension of nanoparticles,with a composition ratio of 10:30:2 Active Agent 4:ethylcellulose:NaTC.The particle size of the nanoparticles in the aqueous suspension wasdetermined using dynamic light scattering (DLS). The average diameterwas found to be 100±35 nm.

For storage in powder form, nanoparticles were lyophilized with anaqueous solution containing a dextran polymer derivative. Example 7 wasformed using Polymer 18, Example 8 was formed using Polymer 19, andExample 9 was formed using Polymer 16. To obtain the driednanoparticles, 1.5 mL of aqueous solution containing 60 mg polymer (40mg/mL) (adjusted to pH 7.4), was added to 3 mL aqueous nanoparticlesuspension (15 mg/mL), and the suspension was lyophilized overnight toobtain a dry powder. The composition ratio of the dried nanoparticleswas about 1:1.3 nanoparticles:dextran polymer derivative.

For comparison, the aqueous nanoparticle suspension was lyophilizedwithout a dextran polymer derivative (Control 1).

Once a solid powder was obtained, the formulations of Examples 7-9 andControl 1 were added to 4.5 mL deionized water at a concentration ofabout 2 mg Active Agent 4/mL and the resulting suspension was vortexed 1minute. Filter potency was used to examine agglomeration ofnanoparticles in the suspension. As nanoparticles agglomerate, thelarger particles are removed via filtration, and the concentration ofsuspended active agent is reduced.

To measure nanoparticle potency, 50 μL of the aqueous nanoparticlesuspension was added to 1 mL methanol and analyzed by high-performanceliquid chromatography (HPLC). HPLC analysis of Active Agent 4 wasperformed using a Zorbax SB C₈ column. The mobile phase consisted of 45%10 mM ammonium acetate, adjusted to pH 4, and 55% acetonitrile. UVabsorbance was measured at 254 nm. Next, the suspension was filteredusing a 0.2 μm filter and analyzed again using HPLC. Percent potencyremaining was calculated by dividing the filtered concentration by theunfiltered concentration. The results are shown in Table 9, and the dataindicate that the nanoparticles remain small and unagglomeratedfollowing resuspension.

TABLE 9 Particle Size of Unfiltered HPLC Potency Suspension 0.2 μmfiltered/ Sample Formulation (nm) unfiltered (wt %) Example 7 ActiveAgent 100 nm ± 15 nm 98 4:Ethocel:NaTC:Polymer 18 10:30:2:55 Example 8Active Agent 120 nm ± 40 nm 81 4:Ethocel:NaTC:Polymer 19 10:30:2:55Example 9 Active Agent 115 nm ± 40 nm 88 4:Ethocel:NaTC:Polymer 1610:30:2:55 Control 1 Active Agent poor fit (suspension 1 4:Ethocel:NaTCprecipitated) 10:30:2

Examples with Small Crystalline Drug/Semi-Crystalline Drug Example 10

An active agent may be formed into a solid dispersion using a dextranpolymer derivative (such as Polymer 1), for example, by using theprocess described in Example 1. The active agent in the dispersion maybe 10 wt % to 50 wt % of the total mass of the dispersion. More than 90wt % of the active agent in the dispersion may be in a non-crystallineor amorphous form.

The dispersion may then be exposed to elevated temperature (e.g., atleast 40° C.) and humidity (e.g., at least 50% relative humidity) for aperiod of time ranging from 4 hours to 72 hours. The resulting materialforms small crystals of active agent or semi-crystalline active agentwith characteristic diameters of less than about 400 nm as measured bytransmission electron microscopy (TEM) analysis, or shows broadened ormissing peaks relative to pure active agent when analyzed via PXRD.

In a disclosed embodiment, a pharmaceutical composition comprises (a)from 0.01 to 99 wt % of an active agent; and (b) from 1 to 99.99 wt % ofa dextran polymer derivative, wherein said dextran polymer derivative isselected from dextran acetate, dextran propionate, dextran succinate,dextran acetate propionate, dextran acetate succinate, dextranpropionate succinate, dextran acetate propionate succinate, and mixturesthereof. In some embodiments, said dextran polymer derivative isselected from the group consisting of dextran acetate, dextranpropionate, dextran succinate, dextran acetate propionate, dextranacetate succinate, dextran propionate succinate, dextran acetatepropionate succinate, and mixtures thereof.

In another disclosed embodiment, a pharmaceutical composition comprises(a) from 0.01 to 99 wt % of an active agent; and (b)from 1 to 99.99 wt %of a dextran polymer derivative, wherein said dextran polymer derivativeis selected from dextran acetate, dextran propionate, dextran succinate,dextran acetate propionate, dextran acetate succinate, dextranpropionate succinate, dextran acetate propionate succinate, and mixturesthereof, wherein said active agent and said dextran polymer derivativeconstitute at least 50 wt % of said composition. In certain embodiments,said dextran polymer derivative is selected from the group consisting ofdextran acetate, dextran propionate, dextran succinate, dextran acetatepropionate, dextran acetate succinate, dextran propionate succinate,dextran acetate propionate succinate, and mixtures thereof, wherein saidactive agent and said dextran polymer derivative constitute at least 50wt % of said composition. In some embodiments, at least 50 wt % of saidcomposition is comprised of said active agent and said dextran polymerderivative. In other embodiments, at least 75 wt % or at least 90 wt %of said composition consists essentially of said active agent and saiddextran polymer derivative.

In any or all of the above embodiments, the composition may consistessentially of said active agent and said dextran polymer derivative. Inany or all of the above embodiments, the composition may comprise aplurality of particles comprising said active agent and said dextranpolymer derivative. The composition may be in the form of a coating on asubstrate.

In any or all of the above embodiments, the composition may be in theform of a solid dispersion of said active agent and said dextran polymerderivative, wherein at least 90 wt % of said active agent in saiddispersion is non-crystalline. The composition may be in the form of asolid solution of said active agent and said dextran polymer derivative.

Alternatively, the composition may be in the form of nanoparticlescomprising said active agent and said dextran polymer derivative,wherein said nanoparticles have an average size of less than 500 nm.

In other embodiments, the composition may comprise a) nanoparticlescomprising said active agent, wherein said nanoparticles have an averagesize of less than 500 nm; and (b) a resuspending material comprisingsaid dextran polymer derivative; from 5 wt % to 90 wt % of the combinedmass of (1) said nanoparticles and (2) said resuspending materialcomprises said resuspending material.

In still other embodiments, said active agent is present in said dextranpolymer derivative in a form selected from at least one of crystallineand semi-crystalline active agent having a size of less than 400 nm inat least one dimension.

In any or all of the above embodiments, the dextran polymer derivativeis aqueous soluble over at least a portion of the pH range of 1-8.Alternatively, the dextran polymer derivative may be poorly aqueoussoluble over at least a portion of the pH range of 1-8. In someembodiments, the dextran polymer derivative is an enteric polymer.

In any or all of the above embodiments, the dextran polymer derivativeis selected from dextran succinate, dextran acetate succinate, dextranpropionate succinate, dextran acetate propionate succinate, and mixturesthereof. In certain embodiments, the dextran polymer derivative isselected from the group consisting of dextran succinate, dextran acetatesuccinate, dextran propionate succinate, dextran acetate propionatesuccinate, and mixtures thereof. In some embodiments, said dextranpolymer derivative is selected from dextran acetate succinate, dextranpropionate succinate, dextran acetate propionate succinate, and mixturesthereof. In certain embodiments, said dextran polymer derivative isselected from the group consisting of dextran acetate succinate, dextranpropionate succinate, dextran acetate propionate succinate, and mixturesthereof.

In any or all of the above embodiments, the dextran polymer derivativemay have the following degree of substitution (DS) for acetate,propionate, and succinate substituents: DS_(acetate) ranges from 0 to2.8; DS_(propionate) ranges from 0 to 2.8; and DS_(succinate) rangesfrom 0 to 2.8. In some embodiments, said degree of substitution forsuccinate is at least 0.05.

In any or all of the above embodiments, the dextran polymer derivativemay have a molecular weight ranging from 3000 daltons to 100,000 daltonsor from 3000 daltons to 70,000 daltons.

In some of the above embodiments, the pharmaceutical composition isformulated for oral delivery, and said dextran polymer derivative is atleast one of aqueous soluble and enteric. In other embodiments, thecomposition is formulated for inhalation, and said dextran polymerderivative is at least one of aqueous soluble and enteric. In stillother embodiments, the composition is formulated for parenteraldelivery, and said dextran polymer derivative is at least one of poorlyaqueous soluble and enteric. In other embodiments, the composition isformulated for intravenous delivery, and said dextran polymer derivativeis at least one of poorly aqueous soluble and enteric. In yet otherembodiments, the composition is formulated for ocular delivery, and saiddextran polymer derivative is at least one of poorly aqueous soluble andenteric.

In some of the above embodiments, the dextran polymer derivative isdextran acetate. In other embodiments, the dextran polymer derivative isdextran propionate, or dextran succinate, or dextran acetate propionate,or dextran acetate succinate, or dextran propionate succinate, ordextran acetate propionate succinate.

A dosage form may comprise the composition of any one of the aboveembodiments, wherein at least 5 wt % of said dosage form is comprised ofsaid composition. In some embodiments, at least 10 wt % of said dosageform, or at least 20 wt % of said dosage form, or at least 25 wt % ofsaid dosage form consists essentially of said composition. In certainembodiments, the dosage form is in the form of a dry powder, or a tabletor capsule, or a suspension.

A method of treating an animal in need of therapy comprisesadministering the composition of any one of the above embodiments to ananimal via a mode selected from oral, buccal, mucosal, sublingual,intravenous, intra-arterial, intramuscular, subcutaneous,intraperitoneal, intraarticular, infusion, intrathecal, intraurethral,topical, subdermal, transdermal, intranasal, inhalation, pulmonarytract, intratracheal, intraocular, ocular, intraaural, vaginal, andrectal. In some embodiments, the composition is administered to ananimal via a mode selected from the group consisting of oral, buccal,mucosal, sublingual, intravenous, intra-arterial, intramuscular,subcutaneous, intraperitoneal, intraarticular, infusion, intrathecal,intraurethral, topical, subdermal, transdermal, intranasal, inhalation,pulmonary tract, intratracheal, intraocular, ocular, intraaural,vaginal, and rectal.

The terms and expressions which have been employed in the foregoingspecification are used therein as terms of description and not oflimitation, and there is no intention in the use of such terms andexpressions of excluding equivalents of the features shown and describedor portions thereof, it being recognized that the scope of the inventionis defined and limited only by the claims which follow.

1. A pharmaceutical composition comprising: a dry powder comprisingparticles suitable for inhalation and having a mass median aerodynamicdiameter of from 0.5 to 100 μm, said particles comprising (a) from 0.01to 99 wt % of an active agent; and (b) from 1 to 99.99 wt % of a dextranpolymer derivative, wherein said dextran polymer derivative is selectedfrom dextran acetate, dextran propionate, dextran succinate, dextranacetate propionate, dextran acetate succinate, dextran propionatesuccinate, dextran acetate propionate succinate, and mixtures thereof.2-4. (canceled)
 5. The composition of claim 1 wherein said particlesconsist essentially of said active agent and said dextran polymerderivative. 6-7. (canceled)
 8. The composition of claim 1 wherein atleast 90 wt % of said active agent is non-crystalline.
 9. Thecomposition of claim 1 in the form of a solid dispersion of said activeagent and said dextran polymer derivative, wherein at least 90 wt % ofsaid active agent in said solid dispersion is non-crystalline.
 10. Thecomposition of claim 1 in the form of nanoparticles comprising saidactive agent and said dextran polymer derivative, wherein saidnanoparticles have an average size of less than 500 nm.
 11. Thecomposition of claim 1 wherein said composition comprises (a)nanoparticles comprising said active agent, wherein said nanoparticleshave an average size of less than 500 nm; and (b) a resuspendingmaterial comprising said dextran polymer derivative; wherein from 5 wt %to 90 wt % of the combined mass of (1) said nanoparticles and (2) saidresuspending material comprises said resuspending material.
 12. Thecomposition of claim 11 wherein at least 75 wt % of said active agent insaid nanoparticles is crystalline.
 13. The composition of claim 1wherein said dextran polymer derivative is aqueous soluble over at leasta portion of the pH range of 1-8.
 14. The composition of claim 1 whereinsaid dextran polymer derivative is an enteric polymer.
 15. (canceled)16. The composition of claim 1 wherein said dextran polymer derivativeis selected from dextran succinate, dextran acetate succinate, dextranpropionate succinate, dextran acetate propionate succinate, and mixturesthereof. 17-20. (canceled)
 21. The composition of claim 1 wherein saiddextran polymer derivative has a molecular weight ranging from 3000daltons to 70,000 daltons. 22-30. (canceled)
 31. The composition ofclaim 1 wherein said dextran polymer derivative is dextran acetatesuccinate.
 32. The composition of claim 1 wherein said dextran polymerderivative is dextran propionate succinate. 33-41. (canceled)
 42. Thecomposition of claim 1 wherein said composition is suitable for deliveryto the lower airways via inhalation through the mouth.
 43. Thecomposition of claim 42 wherein said particles have a mass medianaerodynamic diameter of from 0.5 to 10 μm.
 44. The composition of claim1 wherein said composition is suitable for delivery to the upper airwaysvia inhalation through the nose.
 45. The composition of claim 44 whereinsaid particles have a mass median aerodynamic diameter of from 10 to 70μm.
 46. The composition of claim 1 wherein said composition is suitablefor delivery to the upper and lower airways.
 47. The composition ofclaim 1 wherein said particles are formed by spray drying said activeagent and said dextran polymer derivative from a solution comprisingsaid active agent and said dextran polymer derivative dissolved in asolvent.